Good afternoon, and welcome to the BioVie virtual KOL event. At this time, all attendees are in a listen-only mode. A Q&A 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. I'd now like to turn the call over to Clarence Ahlem, Senior Vice President of Operations at BioVie. Please go ahead, Clarence. Hi. Hi, 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, and I'm the scientific lead for the Parkinson's Disease Project. Today's event will feature presentations from two of our advisors, Dr. Suzanne de la Monte and Dr. Mark Stacey. Dr. de la Monte is a physician and scientific researcher at Brown University, where she is Professor of Neurosurgery and Professor of Pathology and Laboratory Medicine. She coined the term "type 3 diabetes" to bring attention to the influence of insulin resistance and metabolic dysregulation in the pathophysiology of Alzheimer's disease. She will be speaking to us about the relationship between inflammation, insulin resistance, and oxidative stress in neurodegenerative disease. Dr. Stacey is our Principal Clinical Advisor for the Parkinson's Program. Dr. Stacey is a Professor in the Neurology Department of the College of Medicine at Medical University of South Carolina, where he holds the chair for the William E. Murray Professor of Neurology. Dr. Stacey is a former member of the International Executive Committee for the Parkinson's Disease and Movement Disorder Society, and he served on the Executive Committee of the Parkinson's Study Group. His academic focus is on impulse control disorders and non-motor symptoms in Parkinson's, in addition to his interest in drug development for movement disorders. Dr. De la Monte will be leading off, and I will follow her with a short presentation of how Bezisterim's mechanism of action is relevant to many of the things that Dr. De la Monte will discuss. Dr. Stacey will follow me and discuss non-dopaminergic Parkinson's disease therapy and our ongoing clinical study, Sunrise PD. Dr. De la Monte, the floor is yours. Good morning. I'm going to give you an overview of Parkinson's disease and the mechanisms by which that type of neurodegeneration occurs. Next slide, please. Parkinson's is easy to recognize by its motor dysfunction, as shown in the cartoon. Patients have slow motion, slow movements, rigidity, tremor, reduced arm swing, and a shuffle gait. These people are—the diagnosis is readily learned to be recognized even by medical students. Many of us see this in normal life as we go through transportation, et cetera. The mask-like faces is characteristic. What is the basis for this? In this middle panel here, you can see there are two versions of the substantia nigra. In the healthy person, the dark black lines correspond to the substantia nigra compacta. You can see on the right, on Parkinson's disease patient, where that black line is missing, it's quite pale. What's the explanation? In the healthy patient, you have a lot of pigmented neurons that are basically responsible for dopamine delivery. In the patients with Parkinson's, they have two major problems. One is there's actually a loss of cells. That's why it's so pale. The cells that are lost are largely the pigmented cells, and that's why it looks sort of yellow instead of brown. In addition, there's a so-called Lewy body, which is pointed to in the third lower panel, which is basically this dense core thing surrounded by a halo. I think it's noteworthy that the cells that have Lewy bodies often still have pigment in them, meaning that they can have neurotransmitters. The real problem for all the patients with neurodegeneration is actually cell loss. The question is, why? When the cells are lost, they can no longer transmit neurotransmitters and can't communicate with other cells. That's why the therapeutic maneuvers are meant to replace those lost neuroendocrine functions. Next slide. Parkinson's disease is not one structure. It involves several regions of the brain due to the communications. We focus on the brainstem a lot because that's where it starts. You can see from the figure on the left side that the basal part of the brain is affected in Parkinson's. In the middle series of panels, you can see all kinds of features of the same type of neurodegenerative process, namely the Lewy body gets accumulated. With this occurs oxidative stress, DNA damage, damage to the mitochondria, and impaired function. All of those kind of happen together, although the sequence of events is probably from neuroinflammation, oxidative stress as the original trigger. Why do we go on this pathway to get Lewy bodies and degeneration and selective involvement? No one really knows. On the right, you can see these sort of aggregates that are formed. It's called ubiquitinations. It's like rock-like concretions that decorate the cells and prevent function and more or less add additional inflammation and oxidative stress. Next slide. Parkinson's, what is this? It's basically the second most common form of neurodegeneration. That would be the form of the kinds we understand and are present largely throughout the world, actually. It's only second to Alzheimer's disease. Characteristically, it has motor problems. The motor problems lead to dysfunction. If there is anything that really harms a patient in terms of the lifetime when their brains are still working, it is the motor dysfunction that is really in the way. That needs to be dealt with. The primary targets, as I mentioned, are pigmented neurons in the substantia nigra, but also the locus coeruleus and what we call the dorsal motor nucleus of the vagus or 10. These are the main structures. In addition to that, basal forebrain structures that cross over with other forms of neurodegeneration are affected. They lead to cognitive impairment and add to the basal ganglia dysfunction that is present in the brain. Besides Lewy bodies, the brain and neuronal loss, the brain has neuroinflammation and gliosis, which is basically the scarring and inflammatory processes that keep the cascade going. Next. Besides the classical motor symptoms, it's important to realize that Parkinson's disease can be existing as a motor phenomenon itself. There are patients who have genetic versions that go, they can even go 30 years, and they stay predominantly motor. It's also important to recognize that these cross over with other degenerative diseases, including those that lead to dementia, such as dementia with Lewy bodies, Alzheimer's, frontotemporal lobe degeneration. You can even see it with motor neuron disease. There's this Parkinson's dementia complex of Guam, which is fairly rare. We've actually seen a case here in Rhode Island. Okay, next. In general, Parkinson's disease we regard as sporadic. When we say that, we mean it's aging-driven. You can imagine that if there's a way to block the aging process, make brains younger, you would actually halt that process itself. That's kind of the dream for the fountain of youth for the brain. There are genetic factors. We know there are toxins, exposures to golf courses and the like. There are toxins. There are drugs that can precipitate it. At the bottom line, you still end up with degeneration that involves the same kind of molecular pathways that cause those neurons to die. We know there are infectious like COVID and post-encephalitic influenza that have caused Parkinson's, trauma, the so-called dementia pugilistica of Muhammad Ali, CTE, the football players coming up with Parkinsonian things. These are all things that drive the process of Parkinson's disease in patients. Next. What are these things? We put them under this umbrella term of synucleinopathies. In so many ways, I think that's a misnomer because it gives so much emphasis to the inclusions and the alpha-synuclein when there's so much more going on. I think there's so much more going on is why we're here today because those problems are not really addressed. Going from oxidative stress, mitochondrial dysfunction, ER stress, you have lipid damage for the membrane with lipid peroxidation, inflammatory processes, and also impairment of the essential metals that go on in the brain. I think if you think of all these factors, you realize that all of them contribute to making the so-called synucleinopathy. Actually, the neurons that are targeted are there. We really have causal agents that need to be dealt with. Okay, next. In terms of the underlying pathologies, as I mentioned, neuronal loss and scarring, also known as gliosis, we end up with synaptic pathology, meaning that the connections and communications among the cells are somehow impaired. As a result or corresponding with it, we have protein aggregates. These are the ubiquitinated alpha-synuclein compounds, as well as probably others that lead to a reduced homeostatic mechanism. There are intraneural inclusions. Everybody likes to emphasize them. I try to say that there are other factors that are much bigger and need attention. You have this unfolded protein response that drives this circuit of inflammation and oxidative stress. Another target that's not really attended to are the myelin and the oligodendrocytes. We know that those die or undergo degeneration as part of the process. Next. I'm just pointing out here the oxidative stress and the DNA damage that takes place. These free radicals are part of why the cells die. Next. If you're thinking about the underlying pathologies, as I mentioned, there's accelerated aging and there's impaired homeostasis. In the lower part, that intraneuronal material that gets accumulated and aggregated, these five things under there are really responsible for all the processes that take place. Again, the oxidative stress, neuroinflammation, mitochondrial dysfunction, impaired autophagy, and also dysregulated ubiquitin proteasome. In other words, trash buildup in the cells. All of these actually form this reverberating loop where you end up keep going around and around and around. Basically, you're accelerating the aging process that the brain goes from sort of losing it in a slow process to you can see the damage that takes place over time until it's no longer functioning. When you're losing your frontal lobes, the basal forebrain, brainstem, that's when Parkinson's starts to cause so much damage that the patient is disabled. Next. In terms of the diagnosis, I'm not going to spend any time on this at all. Just put it this way. There's no definitive marker. The clinical exam is probably the best of all. There are some peripheral markers that are coming out, but they're not necessarily great. There are some bioindices of what's wrong. Basically, the exam, some objective metrics are what are used for the diagnosis. Okay, next. In terms of the treatment approaches, we obviously have our gang of five here where we use the Levodopa, dopamine agonists, all these same things that are there. None of them actually cure the disease. They just basically treat the symptoms. The concept of using anti-inflammatory, which addresses the oxidative stress inflammation, is out there but not really established as a way to go after the process and actually abate the course of disease. Basically, we're working with symptom management. What we really need are ways to go after the underlying causes that deal with the neurodegeneration. Okay, next. I think that's my last slide. Yeah, I stop there. Stop there. Turn the talk over. Thank you, Dr. de la Monte. I'm going to provide you with an introduction to Bezisterim and its mechanisms of action. For those of you not familiar with Bezisterim, which was previously known as NE3107 and prior to acquisition by BioVie, HE3286, here is the molecular structure. Bezisterim is a novel, orally bioavailable anti-inflammatory agent. It is a sterol, but do not let the steroidal scaffold mislead you. Bezisterim is not bound by and does not target steroid-binding nuclear hormone receptors. It is not a glucocorticoid mimetic. Next slide, please. I will quickly review some of the most important characteristics of Bezisterim. It is orally bioavailable and freely permeates the blood-brain barrier as demonstrated in mice and humans. It targets extracellular signal-regulated kinase in a pathology-specific signaling pathway but does not inhibit homeostasis. Bezisterim decreases tumor necrosis factor expression and activity. There has been no apparent difference to date in adverse events between Bezisterim and placebo-treated subjects. Next slide, please. Bezisterim is promotoric. That is, it improves movement and is neuroprotective in MPTP Parkinson's disease models. It improved motor and non-motor symptoms in our previous phase II study in Parkinson's. That is, the NM101 study. Bezisterim improved cognition in Alzheimer's patients. It decreased DNA methylation-based biological age acceleration in Alzheimer's patients. We hope to see the same impact on DNA age deceleration in our Parkinson's studies. It would have very interesting implications for disease progression. Next slide, please. Bezisterim's mechanism of action is unique. It binds to ERK and a large protein complex that also contains a signaling protein called MAP3K8 along with the NF-kappa B complex and MEK. That is, the mitogen and ERK kinase. This pathway is stimulated by inflammatory mediators interacting with their cognate receptors. It activates ERK and NF-kappa B in this scaffold to stimulate inflammatory cytokine production and tumor necrosis factor receptor 1 activation. It is important to note that ERK is also an essential component of a different scaffold that promotes insulin signaling, and that scaffold is shown in the lower left. Bezisterim does not interfere with ERK in this scaffold. In fact, Bezisterim was originally developed to improve insulin signaling in type 2 diabetes where inflammation causes insulin resistance. Next slide, please. As Dr. de la Monte indicated, inflammation, insulin resistance, mitochondrial dysfunction, and oxidative stress are causally related. Next slide, please. This slide is an extremely simplified representation of some of the inflammatory signaling pathways that are important to Parkinson's pathophysiology. The important message here is that there are many interacting pathways. NF-kappa B is the master regulator of inflammatory cytokine production. Many drugs have been developed to interact specifically and quite elegantly with various components of this web of inflammation. Unfortunately, most of these drug candidates work well in mouse models of Parkinson's but are not very effective in humans. The complexity of these interactions in human disease has been resistant to anti-inflammatory drugs with narrow mechanisms of action. However, Bezisterim impacts the major inflammation signaling node, NF-kappa B, which we believe distinguishes it from other anti-inflammatory drugs developed for neurological indications. As a reminder, NF-kappa B has many important homeostatic activities, which makes Bezisterim's apparent selectivity for inflammation signaling critical to its potential usefulness in chronic diseases such as Parkinson's. Next slide, please. Inflammation disrupts homeostatic mechanisms in the brain. Glial cells, that is, microglia and astrocytes, have critical functions in support of neuronal activity. Inflammation can change the phenotype of microglia and astrocytes from the more protective and homeostatic M2 and A2 phenotype to more pro-inflammatory M1 and A1 phenotypes, with the distinction between the 2 and the 1 phenotype not necessarily being black and white but more a matter of degree. Inflammatory cytokines controlled by NF-kappa B signaling influence the function of cells and the molecular messengers that are released. Bezisterim acting in the MAP3K8 NF-kappa B 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. Inflammation is a major factor driving motor symptoms in Parkinson's. Neuroinflammatory viral infections such as influenza and COVID can induce transient Parkinsonian behavior without apparent extensive neurodegeneration, although those viral diseases can also trigger neurodegeneration or promote that as well. Their neurodegeneration is not necessarily required for the induction of Parkinsonian behavior. The inflammatory cytokine storm associated with these viral infections is believed to be responsible for the Parkinsonism. In Parkinson's patients, intranasal insulin and GLP-1 receptor agonists can improve PAR3 scores. That is, the movement, the ability of patients to move, even though they do not directly or indirectly impact dopamine availability. In animal models of Parkinson's disease, many of which are created with an inflammatory challenge, various anti-inflammatory treatments improve all aspects of disease, including clinical signs. Bezisterim has provided evidence that it can improve motor function in animal models and in humans, although it has no intrinsic dopaminergic activity. We believe that improving motor function with Bezisterim may have much less potential for treatment-driven motor complications. If it is used in conjunction with Levodopa in more advanced patients, Bezisterim might decrease motor complications as it did in our MPTP Parkinson's marmoset model. Next slide, please. In summary, Bezisterim appears to act specifically to reduce inflammatory signaling. Bezisterim adverse effects have been similar to placebo. Neuroinflammation in Parkinson's disease drives both the symptoms and disease progression. Neuroinflammation drives Parkinson's disease pathology through dysregulation of energy homeostasis, alpha-synuclein folding, and cellular interactions. Last, Bezisterim may reduce inflammation in Parkinson's to improve both motor and non-motor symptoms and slow disease progression. With that, I turn it over to Dr. Stacey. Good afternoon. It is my pleasure to be here and talk about an endeavor that I have long been interested in. Next slide. What I'm interested in is really these compounds and how they affect Parkinson's disease. In 2013, while I was on the editorial board of the Journal of Clinical Investigation, we received the first manuscript of Exenatide in treating Parkinson's disease by the Fulton Group. We thought this was a very interesting manuscript. It was not controlled, but we wanted to bring this manuscript forward. We decided that we would provide an accompanying editorial. Next slide. What they looked at was 45 patients with moderate Parkinson's, which is more advanced than the population we're going to study. They compared them to natural controls for 12 months of injections. At the end of this 12-month period, MDS UPDRS score was 2.7 points better in the active group. There was a 2.2-point decline in the control group. Weight loss was very common in the active groups. Next slide. Our caution at that time was that this study demonstrated that a drug in clinical use for another medical condition can be effectively tested for disease modification of Parkinson's disease using standard clinical measures without biomarkers and without placebo control, all of which is a problem for that. We made a statement that double-blind placebo-controlled trials will be required. Next slide. This is kind of the summary of my career. For 30 years, I've played in dopamine at that one synapse. The drugs that are listed in white are drugs that I've played a part in. The drugs that are darker are before my time. I've been on a number of protocol steering committees to get these drugs approved and have been on FDA steering committee presentations for synaptic drugs, for non-motor drugs, for diagnostic technology, and to get an approval to use AAV implantation in patients with Parkinson's disease. Next slide. While we know that that's a dopaminergic phenomenon, most of Parkinson's are dopaminergic, we do know that Parkinson's disease brains suffer everywhere. We see cognitive changes such as depression, psychosis, impulse control disorders, apathy. Anosmia is very common. Sleep disorders and bulbar problems are very common. Orthostatic hypotension and neurologic dysfunction, as well as pain and constipation, are often seen in this group. That does not live at that dopaminergic synapse. We also find alpha-synuclein throughout the brain and the gut, skin, lacrimal glands, CSF, and blood. These diagnostic markers are being developed for CSF and blood to find alpha-synuclein right now. Next slide. One of the areas of my career is impulse control disorders. I first described this in nine patients in 2000 and met with a great deal of resistance. That initial brief report has proven true. There have been more than 1,200 manuscripts since that time published on this one phenomenon in Parkinson's disease. Next slide. Independently, we now call Parkinson's disease one of the synucleinopathies. The next iteration of movement disorders arguments and discussions will be how do we define a synucleinopathy and how do we differentiate clinical conditions in this new spectrum. Next slide. One of the reasons I am interested in clinical trial development is I'm trying to maybe build a better mousetrap using tools that are well established. I think it's important that we be able to go to the participants in a study rather than make them come to us. We learned this to be much more important in COVID. It's much more difficult to get patients to come to our offices now. During this time, I helped design a protocol called TOPAZ, where I continue to be the DSMB chair. This is a home-based trial looking at xylandronic acid to prevent fractures in people with Parkinsonism. It's funded by the NIAA. In two years, we've enrolled more than 2,600 patients, demonstrating that we can do home-based evaluations quite successfully and effectively. It's important that we standardize our assessments. By having these home-based reviews, I think this will be easier. It's important to train raters to a common standard and then constantly evaluate whether we are reaching that common standard. This is something that may be expensive, but I think it is a reason that we've lost trial proving our primary efficacy variables in trials in the past. We also have to manage our placebo response. You do that with randomization, with sometimes treatment run-in, and protocol design. We also still need to measure the remote assessments versus traditional assessments. One of the reasons I'm most excited about this trial is that BioVie has a group of four sites in which standard assessments are done in a traditional way. We can compare those to the large remote site assessment in which we have standard evaluators. Next slide. I mentioned the placebo response. This is looking at a group of patients that were given the impression they were going to receive either a 25% chance of active drug, 50%, 75%, or 100%. In reality, they all received placebo. You can see that a one-to-one randomization is going to be the thing that is least likely to cause a placebo response. In the past, Parkinson's disease trials have often looked at a two-to-one randomization. Although that is not a contingency listed in the slide, two-to-one would be much more likely to produce a placebo effect. Next slide. We want to develop efficient protocols and prove they work. I think Sunrise PD is a very efficient protocol. It is a phase II double-blind randomized controlled trial with 60 patients enrolled after very careful screening. We will randomize in a one-to-one ratio. Patients will receive oral study drug or placebo twice daily. We have a treatment duration of four months. We will screen to a primary endpoint. The duration of the study is five months when we include the safety follow-up. The study, as I said before, will have four to six traditional sites and then one nationwide centralized site, again, allowing us to see if this really works. I frankly think it will change the way we do research in Parkinson's disease if we're proving that going to patients' home is as effective as patients coming to us. That will improve our enrollment. I think will also improve the cost of doing clinical trials. Next slide. The primary endpoints for this trial is a change in modified our Movement Disorder Society protocol or the MDS UPDRS rating scale. Part three is what we're looking at. We will eliminate rigidity and postural instability since that cannot be assessed remotely. Secondary endpoints are change in the part one and two scores of the MDS UPDRS, a change in baseline from clinical global impression and improvement score, a change in severity scores, and all this at 12 weeks. Next slide. We have some exploratory biomarkers that I think are important for really looking at the global brain and global cellular function. The global brain includes the Parkinson's disease disability questionnaire 39 and the Parkinson's disease sleep scale. I'm sorry, the Parkinson's disease questionnaire is a non-motor questionnaire and a Parkinson's disease sleep scale. Our key exploratory biomarkers are looking at change in DNA methylation to see if we can affect DNA death, really, then plasma markers of inflammation, and finally, a percent change from the exploratory biomarkers. Next slide. So 90 papers after that 2013 paper in JCI, we've had two double-blind placebo-controlled trials in Parkinson's disease. This is the original data from the JCI publication showing the change from control and Exenatide. On the right is the trial looking at intranasal insulin, again, showing a small motor benefit when you compare the two groups. Next slide. Here are the two more recent double-blind protocols. One in 2017 shows that the A diagram shows that the patients recruited to the Exenatide arm were a little bit more advanced than the placebo arm. When you normalize that to look at change in part B, you see there was a benefit from Exenatide. If you look below that, you can see that of the 54 patients that were enrolled in this trial, 53 had injection site reactions. If you look at weight loss, there was significant weight loss in the Exenatide group and significant nausea in the Exenatide group. The trial on the left was just published this year. I'll remind you that these are Lancet publications. People are interested in this compound. The JCI would not have taken that study if it was not really interested in this novel approach. There was a slight benefit at 96 weeks, but really all the way through in this trial. Again, injection site reactions were seen in all of the patients. Nausea was much more common in the Exenatide group, and anorexia was much more common in the Exenatide group. Next slide. Why is this the right time for Sunrise PD and Bezisterim? Bezisterim is not an injectable drug. We just got rid of all of those AEs. I think patients will be much more likely to participate and use an oral drug when compared to an injectable. We have tried many other injectable drugs in Parkinson's disease arena, and they have not really had good uptake. This is a drug that passes the blood-brain barrier quite easily. Clarence has gone through the broad mechanisms for changing inflammation signaling. It has good safety and efficacy profile in the 46 patients who were already treated. They were also on Levodopa. The potential to have an efficacy change in patients already on Levodopa seems smaller to me than in the de novo population. This suggests to me that we will pick up this signal using a less advanced population. Next slide. I think we've designed a trial that will look at decreasing placebo effect by watching the anticipation of treatment and not randomizing subjects with an excessive baseline variability. We're also going to use a one-to-one randomization. All subjects are going to go through an exceptional review by a study team that all have been trained and understand what the goals of the study are. We have developed endpoint assessments and trained a group of highly experienced Parkinson's investigators to review these videos. Where there is not complete agreement in the videos, we have even more experienced investigators to help come to a final scoring for these patients that all can agree on. Next slide. This is a marketing profile by Grand View Research that was just out. Here's where I think this drug would fit if we move to approval. The disease-modifying arrow is at MAO-B inhibitors. We have never proven those drugs to be neuroprotective. Still, we continue to use these in this fashion. I think if we find a disease-modifying drug, we will change the practice of using these drugs. Those are often the first-line drugs we use in Parkinson's disease. If we find that it treats motor symptoms, you'll see that the motor symptom buckets are dopamine agonist, anticholinergics, and Levodopa. I don't think we will supplant Levodopa. I think that's the most effective drug we have. The impulse control disorders that we see in dopamine agonists are a barrier to their use. Anticholinergics with their cognitive difficulty are barriers to their use. Next slide. I thank you for your time. I'll turn that back to Tara. Great. Thank you, Dr. Stacey. At this time, we will be conducting a question-and-answer session with our speakers. 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. Please hold for a brief moment while we pull for questions. Our first question comes from Tyler Bussian at Brookline Capital Markets. Please go ahead, Tyler. Hello. Thank you all for the time and the great presentation. I have two questions related to the presentation. The first one is specifically for Dr. Stacey. In removing the rigidity and instability portions of the UPDRS3, what kind of implications does that have for statistics and powering of the overall result in the trial? We powered the trial based on the modifications. We do think we have adequate power to find the results. As far as modifying the UPDRS, this has been done in other videotape assessments and other trials. While it is not ideal, it is accepted for this to occur. I hope we make it ideal. I'm really interested in the papers that will come out comparing the remote sites versus the traditional sites. Great. Looking forward to that. That will be very interesting. The second question is more for the entire panel. Xanotide was brought up as an example of an insulin sensitivity or GLP-1 receptor agonist being tested in Parkinson's disease. While those results did come out in February, it seems that the drug did not have a significant impact. What makes you feel that the insulin modification along with the anti-inflammatory components of Bezisterim would be more likely to succeed compared to Xanotide? You are muted. Tyler, do you mind repeating the question? Yeah. Xanotide's results came out this last February in The Lancet and demonstrated that while the drug was generally well tolerated, it did not have a significant impact on symptomatic outcomes for Parkinson's patients. I want to kind of poll the entire panel. What makes you feel that the insulin modification in Bezisterim combined with the anti-inflammatory components will be more likely to succeed than Exenatide? Let me talk about it first from the trial standpoint. Injections are much more likely to produce a placebo benefit. They may have lost some of the differences between active and placebo because of the injections, particularly since they had inflammation at the injection sites. We think that a pill will be much better tolerated. We can manage this placebo response through a run-in. I also think that this drug has a higher penetration to the brain. We may be able to get more effective levels. As far as the mechanism, I'll let Clarence answer that. Clarence, you're still on mute. You're still on mute. Okay. Got it. Sorry about that. Mechanistically, we are targeting NF-kappa B, which is the major inflammation signaling node. If you want to look at what's the effect size going to be versus now improving basically insulin signaling, we also improve insulin signaling through the anti-inflammatory mechanism. In many respects, we overlap significantly with the GLP-1 receptor agonist mechanism. We also introduce another level of control for the inflammation in addition to the effects of systemic on systemic inflammation that are driving this. I mean, inflammatory cell infiltration in Parkinson's is a big problem. We have data from preclinical models that show that we help preserve blood-brain barrier function and prevent extravasation of these cells. I think that the combination of all these effects could give us a larger effect. Although the point's been made that they are complementary at some level. Certainly, that could be the case. If I had to pick a single mechanism, I would take the control of NF-kappa B because of its global nature. I think another way to look at this we were discussing before is that you can have a pro-insulin effect with the [ankylotens], but you can also have an anti-negative effect, which I think is the big deal about treating with the NE3107. Because basically, if you're turning off the inhibition, it's kind of the reverse of or a complementary approach to adding a stimulation. Eventually, one can get fatigued or cells can get fatigued or resistance to your stimulatory compound. We see this obviously with the weight loss story. If you're having something that's turning off the inhibitor, that's pretty potent. Between anti-inflammatory and then turning off the inhibitor of insulin signaling, that's a very cool way to strategically go after the problems of insulin and IGF-1 deficiency and resistance in Parkinson's. Fantastic. You are basically stating that the concept is you are working around the natural restrictive methods of the body's system by working through the NF-kappa B axis. Is that kind of the statement? Yes. Fantastic. Thank you all very much for your time. The presentation, again, was very interesting. Great. Thanks for the questions, Tyler. Our next question came from someone from the audience. This has limited enrollment for disease level. What are the parameters for acceptance? We are looking four patients that have not been exposed to dopaminergic therapy other than for perhaps diagnostic purposes. It is a very early group. It is a group that may be nearing time for motor treatment. We're hoping to identify with that group to be able to show improved motor response as well and improvement in other areas. Great. Thank you, Dr. Stacey. The next question, how will non-motor symptoms of Parkinson's disease be taken into consideration during study enrollment since the Howe scale being used measures motor only? The non-motor features of Parkinson's that occur early are going to help us with diagnostic criteria. That includes loss of sense of smell, constipation, and sleep behavioral symptoms. Those are traditionally the earliest signs of Parkinson's that we see. Depression sometimes can occur before we begin to see other motor signs. As far as the practicality of looking at the development of non-motor features, we're going to use a number of those for diagnostic to help us with the diagnosis. The non-motor symptoms usually occur after the motor symptoms. Great. The next question, this one's for you, Joe. Will the new Parkinson's study show results of the benefits of 3107 in better sleep quality due to the decrease in night terror symptoms? Why is BioVie not screaming out loud that 3107 does not have any side effects? I'm going to answer that in two parts. I'm Joseph Plumb. I'm the Chief Medical Officer at BioVie. I think we covered part of the question in the last response from Dr. Stacey. We are looking at a number of these symptoms. In our previous study, we did look at signals in non-motor. We did see in that study improvements in sleep and improvements in restless legs. We did not enrich at that time for any of the REM behavioral disorder symptoms. It is not a specific inclusion in this study. On the other hand, it's something we're very interested in pursuing. Great. Thank you. Our next question is for Clarence. What preclinical data do you have to suggest that Bezisterim can be disease-modifying? In every disease model that we've had for the CNS model that we've studied Bezisterim, there have been neuroprotective effects. In the first, in the MPTP marmoset model, we have very clear preservation of tyrosine hydroxylase-positive neurons. In the mouse model, MPTP mouse model, we had decreased neuron death and stress signals. In the glaucoma model, we had neuropreservation. In the optic neuritis model, we had neuron preservation. In addition to that, we've had lots of data showing we decreased the activity of TNF. TNF is a driver of neurodegeneration. So the combination of all the evidence that we have and the mechanism, we are quite confident that we are going to impact disease progression. Great. Thanks, Clarence. The next question, I understand that Parkinson's patients can participate in this trial from home. Can you please explain how that works? There is a great deal of effort to get the word out for this. If you just go to sunrisepd.com, patients can go to that website and be directed for screening and either directed to be having a home assessment, or if they want to do traditional assessments, they can go there. That is the easiest way, I think. Joe, any insight there? Yeah. In terms of practicality, it means we are sending out people to the home. We will have nurses who will be supervised by physicians, all the blood work, all the physical examinations. All of those things happen in the comfort of the patient's own home. The examinations are recorded on video and then rated remotely. The remote raters, as Dr. Stacey has indicated, are highly trained motor disorder specialists. You get the best of both worlds. You get to do this study at home in exactly the same way you would do it if you were to go to the clinic. You get rated by those same physicians. We're pretty happy with this. It means that everyone in the lower 48 contiguous United States who wishes to be in the study and who qualifies will be eligible to have someone come visit the home and do the study. Great. Thank you both. The next question, is it possible that some patients drop out of the trial because their symptoms continue to get worse, either because they are on placebo or Bezisterim does not work? And how will these patients be reflected in your trial result? That is one of the endpoints that we have, to measure the discontinuation rate between treatment groups. Of course, it is possible that people will drop out. We are obviously hoping that those on Bezisterim will continue, will receive some relief from their symptoms. The other aspect of this is it is only a three-month study. If you were looking at six months or longer, certainly that potential would be greater. For this, I mean, the data will tell us, but we will be able to account for it and use that information. Great. Thanks, Clarence. Our final question, I know this is a presentation focused on Parkinson's, but can you please give a brief statement about the status of any BioVie plans regarding the Alzheimer's program? Yeah. I'm happy to answer that again, Joseph Plumb. We are highly interested in pursuing Alzheimer's. This is simply a matter of funding and getting going. We have a good understanding of what we believe to be our response population. We were very happy with the adverse event profile on those patients who followed the protocol. We're ready to go as soon as we have cash on hand. Great. Thanks, Joe. This concludes the Q&A session for today. I'll turn it back to Clarence for some closing remarks. We reviewed here today the mechanisms by which inflammation and oxidative stress and insulin resistance can drive both the motor symptoms and disease progression in Parkinson's. We have reviewed the design of our study here to show how we are set to capture the impact of this reduction of inflammation, first primarily on the reduction of motor symptoms. Importantly, I think in this study, we will also be looking at the DNA methylation result, which we have captured in two other studies we have had in Alzheimer's studies. We believe that that signature will also be present in this. People have been—it's a growing body of information that suggests that this decrease in age acceleration or actually the increase in age acceleration correlates with disease progression in Parkinson's. We believe that even in this short three-month study, we will have a picture into the future as to the potential for disease progression in a way that others simply do not have at this point in drug development. That is going to then provide the foundation for us to move forward to a disease progression study. That is really what the Sunrise PD is all about, providing that foundation to move forward. Great. Thanks, Clarence. This concludes today's event. You may now disconnect. Thank you.