BioVie Inc Aktie

Hello. This is Craig Brelsford with Red Chip Company. Thank you for joining today's event with BioVie, which trades on the NASDAQ under the ticker BIVI. With us today is Cuong Do, President and CEO of BioVie. We will begin with a brief presentation in a moment, and then we will answer your questions. Welcome to everyone joining us today on X, YouTube, LinkedIn and other social media platforms. [Operator Instructions] Before we begin, please allow me to read the safe harbor statement. This call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements pertaining to future financial and/or operating results, along with other statements about the future expectations, beliefs, goals, plans or prospects expressed by management constitute forward-looking statements. Any statements that are not historical facts should also be considered forward-looking statements. Of course, forward-looking statements involve risks and uncertainties. Cuong, please go right ahead.

Thank you, Craig, and thank you, everyone, for joining this afternoon. My name is Cuong Do. I'm the President and CEO of BioVie. At BioVie, we have 2 assets. Our lead asset is a drug called bezisterim, which modulates the production of TNF alpha. So in clinical trials, bezisterim has shown that it can reduce inflammation and reverse the associated insulin resistance. Parkinson's patients have been seeing improved muscle control, Alzheimer's patients have seen a 68% slowing of cognitive decline after just 6 months of treatment, and everyone have seen lower levels of DNA methylation, which essentially is a modulation of the biological aging process. Our second asset is a drug candidate named BIV201, which has the potential to be the first therapy for ascites, which is a terrible end-stage liver disease condition that has greater than 50% mortality within 12 months. We have 2 very near-term catalysts. The top line readout for our Parkinson's trial is now expected in the summer of this year, right, so in the next month or 2. And then our long COVID trial should be -- is expected to have top line readout in late summer and perhaps early fall. And as our company, we are all about inflammation and insulin resistance, right? And how that starts is really in Parkinson's. We believe that the current perspective on Parkinson's is too limiting, too limited. The medical community currently view Parkinson's as a disease that's characterized by loss of muscle control and driven by insufficient levels of dopamine in the brain. That is required, of course, but we believe that is too narrowly defined and misses on 2 critical dimensions. The first is that it ignores the non-motor symptoms that Parkinson's patients have. So for years before the actual diagnosis of Parkinson's, these patients start to experience non-motor symptoms that has to do with sleep disorders, anxiety, depression and cognitive slowing, such that by the time the motor diagnosis is made, over 90% of patients already have experienced these non-motor symptoms for years. And unfortunately, these non-motor symptoms are currently just ignored because very people pay attention to it or believe nothing could be done, right? And of course, the current Parkinson's therapies are not able to address these non-motor symptoms. The second reason is too narrowly considered is that it disregards the underlying metabolic drivers for the disease that essentially starts with inflammation and insulin resistance. And we believe that future treatments should address both motor and non-motor symptoms, and we believe it also needs to address the underlying metabolic drivers, right? The metabolic driver starts with insulin resistance because it's been known for decades now that 2 conditions need to be present at the same time for someone to develop Parkinson's symptoms. The first, of course, is low dopamine levels, but the second is insulin resistance. But if you're able somehow to reverse the insulin resistance, the body adjusts and has been able to make use of the dopamine that's there. But unfortunately, over the decades, nothing has been done to be able to reverse the neuroinflammation and the associated insulin resistance in the brain. As such, all treatment approaches up until now has been to increase the level of dopamine so that you can restore muscle control through the use of a drug called levodopa. Now levodopa is a terrific drug, and that's why it remains the standard of care 5 decades after it was first introduced. It's a terrific drug in helping Parkinson's patients restore muscle control. But it does have limitations, one of which is that it has a very short half-life. And that means patients end up having to take it 2, 3, 5 times a day, and that could become problematic overnight as you sleep because as you sleep, the drug wears off. And when you get to the morning, Parkinson's patients can't move. They can't get out of bed. And that's the reason why Parkinson's patients do not like to schedule anything first thing in the morning because when they wake up, they take their morning medication, wait an hour and bed for the medication to kick in before they can actually start to move and get out of bed, right? So that's one very significant limitation. But perhaps the most dire limitation is that Parkinson's fundamentally is a neurodegenerative disease. That means the longer you have the disease, more and more of your neurons essentially have died away. So the way to address that is you actually have to end up taking higher and higher doses of levodopa. But as you get into higher doses, it leads to something called levodopa-induced dyskinesia, which is the uncontrollable jerky motion that you see Parkinson's patients have. And when you get to dyskinesia, all you can do is reduce your levodopa dose. And as you cut back on the dose, you lose muscle control, right? So it's a terrible situation that Parkinson's patients have, but it's a situation that we believe bezisterim can help address because in preclinical studies in rodents and in nonhuman primates in monkeys, we found that bezisterim alone was equally effective as levodopa in restoring muscle control. Now that's a huge statement in and of itself because no other agent has been able to match levodopa in its ability to restore muscle control over the decades. But what we also found is when you use bezisterim in combination with levodopa, you get a synergistic effect. You saw maximum muscle control. This is being a disease score, a lower score is better. So this is better muscle control. But what got us and our experts most excited is that at the end of the study, when we sacrificed the monkeys and looked at their brains, we found that those who were treated with bezisterim and levodopa retained twice as many neurons as those who were treated with levodopa alone, suggesting that there is a neuroprotective property in the drug. And that to us is not at all surprising because we know bezisterim reverses insulin resistance. That means there's greater glucose available in the brain for neurons. We also know that bezisterim enhances blood flow to the brain, and that means there's greater oxygen available in the brain. So when you have greater oxygen and glucose availability, that only bodes well for better neuronal health. So based on this information, we went into the clinic and enrolled 40 moderate to severe Parkinson's patients and essentially replicated in humans the study that we did with the monkeys. We enrolled half the patients in an arm that gave them a placebo and levodopa, so essentially levodopa alone as shown in red. The other half were given the combination of bezisterim and levodopa as shown in blue. And what we found essentially was the same as what we saw in the monkeys. Essentially, those that were given the combination had significantly greater muscle control than those that were treated with just bezisterim alone. In addition, we found that roughly 1/3 of those that were given the combination had their muscle in what's called the on state first thing in the morning, meaning that they had control of their muscles. They can get out of bed first thing in the morning before they take the morning medication, whereas none of those that were given just the levodopa alone had the ability to move first thing in the morning. The other thing that we found was interesting is that we started to see a signal that bezisterim has some effect for non-motor symptoms, namely these 40 patients, a number of them told us that they actually had better sleep. They had actually better anxiety and depression scores and so forth, right? So here, with this study, we have established human proof of concept that you can use bezisterim in combination with levodopa to help moderate to severe Parkinson's patients improve their muscle control. And this establishes the first half of what we want to do in Parkinson's. And we are now concluding a study to establish the second half of what we want to do, which is to use bezisterim alone with Parkinson's patients at a much earlier stage in their disease. We enrolled 60 patients who are needing to go on to therapy for the first time to address their symptoms. Half of those patients were given a placebo and the other half were given bezisterim. And the trial aims to show that bezisterim can help these patients address both their motor and non motor symptoms, right? This trial has completed the patient-facing portion. The last patient has already come in for his or her last visit. And we are now in the process of essentially cleaning the data, waiting for biomarker results to come back in the labs, which is frankly the thing that's taking the longest time. And once we have all the data, we'll lock the database and start the analysis of the data. So if everything goes according to plan, we hope to announce the results of this data within the next month or 2. Let's call it sometime in late July, early August is when we hope to have results from this Parkinson's trial. And once fully developed, we believe that bezisterim could become the first therapy -- first new therapy in Parkinson's in over 5 decades. It has the potential to be the first therapy to address both motor and non-motor symptoms of the disease. And it has the potential to be the first therapy to potentially modify the progression of the disease, namely slow the progression of the disease, right? And when fully developed, this, we believe can become the $3 billion to $5 billion annual sales opportunity in the U.S. alone. So let me now move on to Long COVID, right? And you may ask -- be asking yourself, why are we talking about long COVID and what does this have to do with Alzheimer’s and Parkinson's. And the honest truth is we had no idea ourselves when we started on this journey. It was our experts who helped us understand the situation. I've had long COVID -- I had COVID now 3 times. And I kept myself among the lucky majority of people who have COVID, namely when we had the infection, our immune system kicked in, got rid of the virus, the body returned to normal, life went -- goes on as usual. And that's why the whole world essentially thinks that COVID is long behind us, right, despite the fact that there are 30,000 people who are still getting COVID each day right now. But there are 17 million Americans who do not have it so lucky. So these 17 million continue to suffer the lingering after effects of the infection that shows up as brain fog, fatigue and severe post-exertional malaise. 3 million have it so badly that they've had to quit or change their jobs simply because they can no longer keep up with the physical demands of their jobs. Many of them essentially are on disabilities. And within the last couple of years, researchers have tied these long COVID symptoms to inflammation that works through something called the TLR 4, the toll-like receptor 4, which leads to the reduction of TNF alpha, which, of course, is exactly where our drug [indiscernible] affects. And what's really going on with these patients, what's believed to be going on with these patients is that after their immune system got rid of the virus, they still have fragments of the spike protein and the envelope protein continuing to circulate in their bodies. So while there's no active infection, their bodies believe that there is still -- their immune system still believe that there is one. So the immune system is constantly mounting a response and that, that goes through that immune response is producing a lot of TNF alpha, which is the inflammation, which is then associated with these long COVID symptoms, right? That's what our experts helped us to understand. These experts also told us about a grant program that we applied to where we received a $13 million grant. We're the only organization, right, company nonprofit organization of any kind that received a grant to test the therapeutic to see if we can address these CNS symptoms of long COVID of brain fog malaise fatigue. Using that grant, we have enrolled 200 patients in a trial with the help of some of the best leading long COVID centers out there, places like Yale, Mount Sinai, Mayo Clinic, UCSF, Stanford and so forth. That helped us enroll 200 patients in a trial that randomized half to placebo and the other half to bezisterim. And we are exploring a number of endpoints having to do with cognition malaise, fatigue and a number of biomarkers as well. This is an exploratory study that's looking at about 20 of these different endpoints. This trial is now fully enrolled. Yale enrolled the last patient a couple of weeks ago, which would put it on track to have the last patient come in with the last visit sometime in early August, early to mid-August, which means that we should be in a position to have top line data readout at the end of August to early September as well, okay? And when -- and the data really looks promising. And if we get the promising results upon unblinding that we hope to see, -- this would allow us to go to the FDA in the fall to have a conversation about an accelerated approval or an emergency use authorization. And we believe we can get a breakthrough designation for this as well. And that, we believe, would make us a strong takeover target or partnering target for big pharma companies out there. And we believe Long COVID could represent a $10-plus billion annual sales opportunity in the U.S. alone. Just recognizing the time here, let me stop it here, and let me recap where we stand. We believe that BioVie represents a terrific opportunity for investors. We have a -- we have 2 imminent data readouts in the coming months. We have sufficient cash to last towards the tail end of the year. And despite that, we are still lumped in with other biotech microcaps, whereby our current market cap is $10 million, which is a fraction of our current cash balance. And that's the reason why I believe we represent a terrific investment opportunities for investors who have a 12-month planning horizon. And I say that not only because I'm the CEO of the company. I also am one of the largest shareholders of the company as well, right? And I have significant amounts tied up in the company over the years. With that, let me stop it here and open up for any questions you may have. Thank you.

Thank you very much Cuong, [Operator Instructions]. Cuong we've already received several great questions here. Here's the first one. BioVie has 2 clinical top line data readouts expected in the coming months. Can you give us any more details about those?

Well, I cannot really give much more because right now, our team is going through the process of conducting the trial. What I can tell you is that we look at the data on a regular basis as they come in on a daily basis, primarily to monitor for safety just to make sure that the drug is safe, right? And as of now, bezisterim continues to essentially replicate what we know from historical trials, namely, it's been very, very safe. There are no drug-related severe adverse events, very few adverse events at all. right? We also see from the blinded data, a promising pattern of separation, whereby some people get better, some people get worse and some people stay the same, right? And if the ones who got better are the ones that are on drug upon unblinding that these 3 studies would represent a terrific move steps forward for the patient community. So all we can really tell right now is in Parkinson's. We are cleaning the data and getting ready for database lock as we wait for the biomarker data to come back from the vendors. And on long COVID, the patients are going through the trial, the monitoring process. They're taking their drugs, they're coming in for visits periodically, and we should have the last patient -- last visit in the early to mid-August time frame. Hopefully, that answers your question.

As you made clear in your presentation, you think you are different from most of the world that thinks that Parkinson's disease is caused by low dopamine levels leading to loss of motor control. You point to inflammation. Can you tell us more, please?

Well, let me answer that by starting with a very basic biology review, right? Every cell in our body needs energy to function. And that energy comes in the form of glucose. You may remember from your high school biology, how glucose remember the crep cycle and how that produces ATP and so forth. So it all starts with glucose. And when it comes to glucose regulation, insulin is the key factor. So think of insulin as a key that has to fit into a lock a receptor on the surface of every cell in the body. That receptor is called the insulin receptor substrate 1 and 2. So insulin has to fit -- it's a key that has to fit into the lock so that it can open it cell, the cell could then absorb and take in glucose. But when you have inflammation, that's TNF alpha, TNF alpha also triggers and drives something called JNK n IKK that also binds to the IRS 1 and 2. So think of inflammation as rust. It's the rust that builds upon your lock. And when you have a rusting lock, the insulin key cannot fit in and therefore, it cannot open the door for glucose to come in. So as a result, cell starts to malfunction and over time, cells die. And recall that neurons are among the most power-hungry glucose hungry cells in your body, okay? And when you have inflammation that leads to insulin resistance, it affects the entire brain. So if you have a problem that starts with substantial nigra, that leads to Parkinson's because those cells that use and make dopamine starts to die. If the problem comes in other parts of the brain, you then can have problems with Alzheimer's, ALS and so forth, right? So inherently, it starts with inflammation leading to insulin resistance that provides the metabolic driver of many of these neurodegenerative diseases, starting with Parkinson's going on to Alzheimer's and many others. I hope that answers your question.

Yes, it does. Thank you very much, Cuong. Thank you, everyone, for all your great questions. We've got many coming in here. Cuong, is there a pronounced placebo effect for Parkinson's brain wise? The emotion of hope causes the release of dopamine, which may influence results? And how do you control for that effect?

That is a great question. Thank you so much for that. And you are absolutely right in saying that there is a potential for a high placebo effect in conducting Parkinson's trial. Just the fact that you're thinking about it or doing something about it could lead to a higher release of dopamine. So we have done several things that are quite innovative in this trial. First, to avoid any placebo effect that people may have just by the mere fact that they're leaving their house and coming into a clinical site. We actually set nurses out to their homes, to conduct the assessments, right, to reduce the variability of what's going on. And so we basically try to keep people in their same environments just not to trigger any anxiety or anything that could create a placebo effect. But nurses would go to the patient's home. All the activities there are recorded by video and all the videos across all of the patient's home, across all of the clinical sites are then scored by a central radar so that you, again, do not have variability. You have a single person reviewing all the videos from all of the patients, right? so that you then have consistency across all of that. And that helps reduce the placebo effect by having patients in their home. It helps reduce variability by having a single reader. The second thing that we did to try to avoid the placebo effect is to -- in our protocol, we designed in what's called a placebo run-in, which is patients would come in with -- or the nurses would go out with the first visit, call it, visit 1, and we would assess their activities and so forth on the various scales that we use. And we wait 30 days and then we repeat that again, right? And if there's been a change in the various assessments, but that's most likely a placebo effect because nothing has been done in that 30 days. No drug has been given or anything like that. So if there was a significant change, then that patient then became ineligible to participate. On if those 2 metrics, those 2 visits were roughly dissimilar where you then randomized into a placebo arm or the drug arm, right? So those are the things that we did to try to minimize and avoid the placebo effect that is common in many Parkinson's trials. Thank you so much for that very perceptive question.

Thanks, Cuong. How do you compare your Alzheimer's disease solution to LEQEMBI and Kisluna?

Well, we are very, very different from the 2 approved drugs. Perhaps the easiest way to answer that is for me to bring up a chart. Give me 1 minute to share my screen. When I first started working in Alzheimer's in the late '80s, everyone, myself included, we focused on the amyloid plaques and the amyloid buildup. So here on this chart, everything that's in blue is a part of the amyloid pathway. Everything in red is a drug that is trying to modify the pathway in some manner, right? And over the years, we started looking at tau and tau tangles as well. But the reality is over those 5 decades, for 5 decades that I've been working at it in Alzheimer's, there's never been a drug that can reduce plaques and tangles and arrest or reverse the cognitive decline in Alzheimer's. And within the last decade or so, more and more researchers are coming around to the point of view that plaques and tangles themselves are not the toxic agent that's causing neurodegeneration, but they're inflammatory in nature. They cause inflammation that works through the TLR4, the toll-like receptor 4 receptor here that we talked about in long COVID or RAGE and other receptors, right? But as you can see, many other things cause inflammation as well. But all of these things share one thing in common. they all activate ERK and NF-kappa B to produce TNF alpha, right? And of course, when you have CNF alpha, you have more cytokines and more APP. APP then leads to more amyloid buildup, right? TNF alpha actually drives the kinase that drives that turns tau into phospho-tau. And we are very different than all the other drugs in that we block the production of TNF alpha right before the production of TNF alpha, which is considered to be the master regulator of inflammation. The drugs that were mentioned, LEQEMBI and lecanemab and donanemab, they actually block -- try to reverse the production of amyloid and block the production of the plaques. And they have -- and the reason I believe that those drugs have only had a limited impact on the disease progression is that the only thing that they're doing is they're reducing the inflammation that's created and are driven by the plaques, but hasn't done anything about the inflammation that's driven by the other factors, right? And that's why they've only seen a very modest impact on cognitive decline, whereas we believe we will have significantly greater impact because we block everything. And as you may know, we had a Phase III trial in Alzheimer's. Using the same endpoint that was used here for LEQEMBI, for example, CDRS-B, we had a 68% slowing of cognitive decline versus placebo after just 6 months of treatment. And to put that into context, the anti-amyloid drugs had as a class, roughly a 30% slowing of cognitive decline versus placebo after 18 months of treatment. And we have had a very mild side effect profile. The #1 reported side effect was a mild headache reported by about 8% of patients, whereas, as you know, the other drugs have had significant concerns about brain swelling, brain bleeding such that they need to be followed by -- monitored by PET. And so we look forward today when we can essentially proceed further and go to the next Phase III trial to show statistical significance of the results that we're seeing here in this trial that has fewer patients. I hope that answers your question.

Thanks, Cuong. Status of the ascites drug, is there a spin-off anticipated?

A great question on that as well. We have, as of now, have received all the feedback that we need from the FDA to proceed to the next step, to essentially conduct the one registrational trial that's required because as you know, we already have orphan and fast track designation. We have filed an S-1 to take a company called Option Therapeutics public. Our intention is when market conditions are right, we will put the ascites drug into Option Therapeutics. We would endeavor to raise $25 million, $30 million or so for that company, and that would allow us to conduct a trial that's needed, right? And we believe that trial will probably take about 2, 2.5 years to conduct and to get it registered, right? So right now, we're waiting for market conditions to be right for us to be able to go out and try to raise about $25 million for the ascites program by floating by taking Ox Therapeutics.

Thank you Cuong.

Can you show the potential revenue chart for Parkinson's, Alzheimer's, Long COVID and ascites Thanks, Cuong, Great job.

I wish I had the most updated chart on that to show that in one place the numbers, I do not. But let me give you the numbers, right? We believe that ascites could be a $1.5 billion to $2 billion annual sales drug in the U.S. alone. We believe that Parkinson's could be a $3 billion to $5 billion annual sales drug in the U.S. alone. Long COVID could represent a $10 billion annual sales in the U.S. And of course, Alzheimer's is going to be the blockbusters that could be a $30-plus billion annual sales product in the U.S. alone, right? And thank you for asking that question. That just reminds me and I could go and put that chart into the next version of the deck.

Thank you very much Cuong.

Let's give everyone a moment to consider any more questions they may have for Cuong Do, the President and CEO of BioVie. [Operator Instructions]

This person wants to know more about collaborations. Could you go into more depth with those collaborations that you mentioned with large pharma for the co-development or out-licensing of bezisterim in specific regions or indications?

We've had a number of conversations with larger pharma companies. And the feedback from them has been pretty consistent, which is they are very intrigued with this mechanism of action and the drug, and they want us to essentially come back to them when we have the clinical results, which I get it. I've been on their side of the table as well, right? What I've learned in big pharma is that no one ever gets fired in big pharma by playing it safe, right? And so pharma -- and as you know, the world out there is littered with promising Alzheimer's and Parkinson's drug that has failed in Phase III, Phase II. And that's why big pharma companies now are quite shy and quite reticent of doing collaborations and deals before you actually get data that actually is much further along. So those conversations have been had. They're on hold. And I think the -- we will reengage when we have additional data, right? And I think COVID could also be a very interesting conversation for us to have in the very near future as well.

Thank you, Cuong.

How much would an Alzheimer's trial cost total start to finish?

That's a very tough question to answer, but let me give you a ballpark. Based upon what we know now and what we have modeled out, we believe that Alzheimer's trial could take $25 million to $30 million to conduct. That's one trial, and we would need to conduct 2 of them, right? So the total cost to bring bezisterim to market for Alzheimer's would be $50 million to $60 -- and that's part of the reason why the program is currently on hold until such time as market conditions would allow us to go and raise the funds, right? That's why we have focused everything so far on Parkinson's and Long COVID because those trials tend to be smaller, easier to do and shorter to conduct.

Will there be any analysis of blinded data on Parkinson's as you did with Alzheimer's?

We are conducting dose analysis right now, and we have been conducting for Parkinson's as we go along. But we purposefully have chosen not to share or release any of them for the reason that was alluded to by -- in an earlier question, which is we want to avoid doing anything that could lead to a placebo effect. If we announce, for example, that, oh, we're seeing great separation with patients, that could lead anybody in those patients in the clinical trials or even the clinicians in the clinical trials to actually start to see things that may not be there. And that's the reason why we have chosen not to say anything or announce anything about the blinded data as we've gone along.

Thanks a lot, Cuong.

Can you recommend where to go to learn more about the mechanism of action and other pharmacological details of bezisterim?

All of the information is currently available at our website. So please to go to our website, which is www.bioviepharma.com. There's a section there that talks about our science where you could go deeper into the science. Under the Investors section as well, you can see links to the KOL events that we have held within the last few years on these indications, right? Just a few weeks back, we had a KOL event on Parkinson's. And about a year ago, we had a KOL event on Long COVID, right? And we are considering doing another KOL event on long COVID in the next couple of months, just to kind of reappoint everyone in the market to what we're doing on long COVID, the causes of long COVID and why we're optimistic bezisterim could help address long COVID, doing all of this to essentially build awareness in advance of our data unveiling late summer, early fall.

It seems that so much of what BioVie is doing is based on its approach to inflammation and aging. Tell us again how your approach to inflammation and aging differs from your biopharma peers.

Frankly, you can count on 1 possibly 2 hands the number of companies that are working in inflammation and CNS diseases out there. The whole world has really focused on in Alzheimer's, for example, on amyloid and tau. And we believe that is just a dead end, right? We have tried for years to basically sound the alarm and say that there is -- that is a dead end, but we're a tiny company. And so as a result, we don't get a lot of attention, and we actually just kind of have to go out there and demonstrate it. So we count ourselves among the 2 handful of companies that are working as working with inflammation as the key driver of disease pathology. What also makes us very different is also our approach on insulin resistance. Because bezisterim blocks TNF alpha, right before it activates JNK and IKK, it actually reverses insulin resistance. Please remember that bezisterim was originally brought into the clinic as a diabetes drug. And in that first trial, it showed exactly what you would want to see in a diabetes drug. It reversed insulin resistance and it brought all these different biological systems back into normal ranges. So glucose, HbA1c, cardiovascular and so forth. But that was before the team truly understood the mechanism of action and how it blocks TNF alpha. And once we understood that, we recognize that bezisterim role is potentially much bigger in the world and in addressing the biggest unmet medical needs right now, essentially Alzheimer's, Parkinson's and a number of other CNS diseases. And I believe that's what makes us very, very unique in the biopharma world out there. We, I believe, have the most unique molecule and leads us to have the most interesting portfolio in the biotech world.

Thanks, Cuong. And we probably have time for a few more questions. We've been getting so many great questions. Thank you so much to all of our participants.

This is medical related here.

So if someone has type 2 diabetes and inflammation and insulin inefficiency, are they more likely to get Alzheimer's?

The answer to that is, unfortunately, yes, absolutely. If you have type 2 diabetes and insulin resistance, statistics shows that you are at a significantly greater risk of developing Alzheimer's, Parkinson's and other CNS diseases. Let me give the statistics the other way around. If you look at Alzheimer's patients, the Mayo Clinic and NHS out of the U.K. have shown that about 80% of Alzheimer's patients have or are developing insulin resistance. The comparable statistics in Parkinson's is about 50% of Parkinson's patients have are developing insulin resistance, right? And so that's the part of the reason why we so strongly believe that many of these diseases have a metabolic underlying underpinning driver to it. And it's not just about just low dopamine or amyloid and so forth. It really starts with TNF alpha, which is the master regulator of inflammation. And when you have TNF alpha, you're going to create insulin resistance and insulin resistance starts to kill off cells. And that's why neurodegeneration is a real problem. That's a link between inflammation, insulin resistance and neurodegenerations in our belief.

All right. We are just at the top of the hour. We'll wrap up here. And if you do have any questions for Cuong Do, no matter whether they were answered today or not, you can write us at [email protected], and we will make sure that Cuong sees your question. For more information about BioVie , again, you can write us at [email protected] or you call us at 1800redchip. Please visit Redship's Investor Information page for BioVie. It's bivinfo.com There, you can view and download the investor presentation and fact sheet and sign up for news alerts on BioVie. Please watch Small Stocks Big Money, Redship's program featuring exciting small-cap companies every Saturday night at 7:00 p.m. Eastern on Bloomberg USA. And finally, please join our next webinar with Foremost Clean Energy tomorrow at 4:15 p.m. U.S. Eastern. Register for all redchip webinars at redchhip.com/events. Thanks again to our many participants today. And as always, thank you, Cuong.

Thank you, everyone, for joining. Have a great day.

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.

Hello. This is Craig Brelsford with RedChip Companies. Thank you for joining today's event with BioVie, which trades on the NASDAQ under the ticker BIVI. With us today, we have Cuong Do, President and CEO of BioVie. We will begin with a brief presentation in a moment and then we will answer your questions. Submit your question at any time by using the Q&A tool at the bottom of the Zoom window.

Before we begin, please allow me to read the safe harbor statement. This call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements pertaining to future financial and/or operating results along with other statements about the future expectations, beliefs, goals, plans or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact should also be considered forward-looking statements. Of course, forward-looking statements involve risks and uncertainties.

Cuong when you're ready, please go ahead.

Thank you, everyone. Thank you for joining today. My name is Cuong Do, I am the CEO of BioVie. At BioVie we have 2 assets that are currently in development right now. Our lead asset is a drug candidate named bezisterim, that's formerly known as NE3107. It's known as a modulator of inflammation. So it modulates the production of TNF alpha. In various clinical trials, many patients treated with bezisterim have experienced reduced inflammation and the associated insulin resistance.

In our Parkinson's trial, Parkinson's patients have seen improved muscle control. in our Alzheimer's trial, Alzheimer's patients have been seen improved cognition and function. And all these patients have also experienced lower levels of DNA methylation, which is essentially in modulation of the biological aging process.

Our second drug candidate where the heritage at the beginning of the company is a drug called BIV201, which is a novel formulation of a drug called [indiscernible], which has the potential to become the first therapy for ascites, which is a horrible end-stage liver disease commission that has greater than 50% mortality rate within a year.

Before we go into the detail, let me give 2 near-term updates on expectations. We have 2 near-term catalysts. As you know, our Parkinson's trial has been fully enrolled since the end of 2025. And those patients are continuing on through the trial. And as such, the last patient is expected to come in for his or her last visit at the end of April. This basically puts us in line to have top line data readouts from this trial in the second quarter of 2026. So that's coming up very quickly, right? So I'm hoping that, that will come by June, hopefully by May. So second quarter of 2026 is when we expect to have top line readout from our Parkinson's trial.

The other guidance -- new guidance that we're giving, is that our Long COVID trial is expected to have top line data readout towards the end of the summer of 2026. This trial has been enrolling very rapidly. Now that all of our large academic medical center partners are online, the large Long COVID sites at Mayo Clinic Yale, Stanford, [ UCSF ], Mount Sinai are all online. They are actively recruiting and enrolling patients right now in that trial. And as such, at the pace that we're going, we expect to have the last patient enrolled by the end of March and perhaps early April at the latest. And that would mean that we will have top line data readout, let's say, in the August time frame of this year. So exciting few months coming up for the company with 2 top line data readout of our Parkinson's and our Long COVID trials.

And as you may recall, we are all about inflammation. Bezisterim blocks the production of TNF alpha and TNF alpha is considered to be the master regulator of inflammation when you have TNF alpha produced, it goes on to create more inflammation creates a forward-feeding pro inflammatory cycle where it produces more [ chemokines ], cytokines and so forth that leads to more inflammation all of which leads then to more TNF alpha. And of course, this has been associated with a large number of diseases. TNF alpha has also been known as a key driver of insulin resistance which, of course, leads to diabetes and various metabolic disorders. TNF alpha has been implicated directly in the driving the serine kinase that phosphorylates [indiscernible] to become [indiscernible] in Alzheimer's disease. And TNF alpha is the key driver, a key driver of something called DNA methyltransferase 3A and B, which leads to the hypermethylation of our DNA which has been associated with a large number of diseases, particularly age-related diseases.

And bezisterim works to block the production of TNF alpha and it works through something called ERK with the extra cellular regulated kinase. Now it's been known for decades that ERK placed 2 very different roles in virtually every cell in our body. The first having to do with insulin signaling where insulin works through ERK for all of its cellular growth repair and regeneration activities. That's known as homeostatic ERK. But ERK also plays an important role in inflammation, whereby various extra cellular signals or agents such as cytokines and [ chemokines ] will enter the cell activate ERK, which in turn activates NF-kappa B and NF-kappa B triggers the production of TNF alpha. So when you have TNF alpha, it then just goes on and create, release more inflammatory factors and create this forward-feeding pro-inflammatory cycle.

So it's obvious what you want to do. What you want is to block inflammatory ERK but not do anything with homeostatic ERK. But unfortunately, that's much easier second done because dozens of teams over decades trying to do it. But no one was able to succeed. Everyone failed because they were not able to create a selective enough inhibitor of just inflammatory ERK. And frankly, that's where NE3107 comes in or bezisterim. And honestly, this is where we got lucky. We did not set out to do this. we just had our eyes open when we recognize what it does. It turns out that bezisterim blocks the activation of ERK in NF-kappa B. As a result when you do not have NF-kappa B activation, you are not going to get TNF alpha, right?

And so when we thought this, it became very clear that bezisterim has a critical role in a number of different disease conditions. Right now, we are focusing on Parkinson's. It has been known for some time for decades, that 2 conditions need to be present at the same time for a person to develop Parkinson's symptoms. The first is you need low dopamine levels in the brain and the second is to need inflammation and the associated insulin resistance. If you're able to reverse the insulin resistance in the brain, the body is then able to make use of whatever low level of dopamine that is currently there, right? And people have tried for a long time, including doing some really crazy things, far out things like, in this case, using inhaled insulin, just trying to get more insulin nose, get it up into the brain to see if you can refer to insulin resistance.

And it does work in this clinical trial, as you can see here, those that received insulin inhaled insulin we're able to improve their muscle control significantly, but this is a disease score. So a lower score is better. So those that were that were treated with insulin saw an improvement of what's called third unified Parkinson's disease rating scale Part III with the muscle or the motor control. But unfortunately, that is just not a very practical solution, right? You can't easily get inhaled insulin out to everybody and treat it and it's just not as effective as you want it to be. It's not very practical.

So to this day, the only practical solution for Parkinson's patients is to use a drug called levodopa that was introduced over 5 decades ago. Levodopa is a terrific drug. What it does is it enhances the dopamine level that's in the brain and therefore, it enhances muscle control and it does a terrific job at that. But it has several problems. One is that it has a short half-life, which means that patients have to take it multiple times a day. which is very inconvenient. But the real problem comes in is overnight when people don't normally wake up in the middle of the night to take their overnight medication. So that means that by the time they wake up in the morning, levodopa has already worn off. It's kind of out of the patient system. So that means they do not have muscle control, they're rigid, they can't get out of bed.

This is part of the reason why Parkinson's patients don't like the schedule in the first thing in the morning is because they can't get on a bed. So they have to stay in bed, take their medication wait an hour or so for the levodopa kick in before they can actually start to move and get out of bed. So that's one significant problem with levodopa.

The second is that the effect of levodopa wears off over time. So that the longer you're on the drug, you end up having to take higher and higher doses or amounts of the drug. And as you get into the higher doses of levodopa, it leads to something called levodopa-induced dyskinesia, which is essentially the trembling that you see many Parkinson's specials have. And when you have the dyskinesia, all you can do is reduce the dose of above, right, and wait for the tremors to pass. But as you cut back on the dose, you lose muscle control. So these patients are in a terrible situation with a terrible trade-off that they have to make, right? We believe bezisterim could be a solution for that. Because in our preclinical studies in both [ ROTAs ] and nonhuman primates, we saw that bezisterim was equally effective as levodopa in restoring muscle control.

Now that's a huge statement in and of itself because over the decades, no drug has been not equal levodopa, right? And with the support of Michael J. Fox Foundation, we -- the original study showed that bezisterim alone was equally affected as levodopa. But we also found that when you give it in combination, when you give bezisterim in combination with levodopa, you saw a synergistic effect. You saw the greatest muscle control. You also saw a reduction in the dyskinesia, but most importantly, we saw that at the end of the study, when we sacrifice the monkeys and look at their brains. Those that were treated with bezisterim retain twice as many neurons as those were not treated with bezisterim suggesting that bezisterim has a neuroprotective property to the drug, which, to us, is not at all surprising because we know that bezisterim reverses insulin resistance, which means there's greater glucose availability in the brain.

We also note that bezisterim enhances blood flow to the brain, which means -- and when you have creator oxygen available in the brain because of greater blood flow and you have more glucose that's only going to bode well for better neuronal health. So based upon that, we went into the clinic and enrolled 40 patients, whereby frankly, we replicated in Parkinson's patients. the study that we did with but nonhuman primates. We gave half the patients of placebo and levodopa as shown in red here, so essentially just levodopa. And then we get the other half bezisterim and levodopa as shown in blue. And after 28 days of treatment, you see that those that were treated with the combination, saw about a 3-plus point advantage on the most -- on the motor score, the Part III score of the Unified Parkinson's disease rating scale. Now that's a clinically meaningful improvement. And that is a huge deal because this is on top of what levodopa alone, let's say, with the produced, right?

And I've said before, levodopa is a great drug. And with the combination with bezisterim, we make it even that much better. But we also found is that those who are younger than 70 years old, presumably whose disease progression has not done so far. That difference is over 4 points. In fact you don't see that you don't see that very often. So this shows that in humans that you can use bezisterim in combination of levodopa to help moderate and severe Parkinson's patients improve under muscle control. We also found that it has a dramatic impact on the overnight effect, right? So as I mentioned before, we saw in our trial has seen every single day by hundreds of thousands of Parkinson's patients. None of the patients that were given a placebo and levodopa or just levodopa, none of them had control of their muscles first thing in the morning, what's called [indiscernible] muscle state, none at muscle control or could get out of bed, where roughly 1/3 of bezisterim patients, has muscle control and could get out of bed.

So this establishes the first half of what we want to do in Parkinson's. Mainly, we have shown that we have now human proof of concept that we can use bezisterim in combination with levodopa to help moderate in severe Parkinson's patients, improve the muscle control. We completed this trial last year, and that's why we are now on to our second trial and that's the trial that's currently underway. In this second trial, we are enrolling 60 patients. who are earlier in their disease state. These are diagnosed Parkinson's patients who need to go on to therapy for the first time. We are giving half of them just a placebo and then the other half, we're giving bezisterim. And what we're hoping -- what we're trying to show here is that those that are treated with bezisterim has sees a delay of their disease progression.

This trial alone would not show that, right? The next trial, the Phase III trial that we will conduct will be for a longer period of time and explicitly what we're trying to show in these combination of trials is thzt bezisterim could become the first drug to modify the progression of the disease to delay the progression of the disease. And that's really the most important thing we're trying to demonstrate for bezisterim in Parkinson's.

But this second trial establishes the second part of what we want to do in Parkinson's. This second trial is fully enrolled now, and we expect to have top line data readout for this trial in the second quarter, hopefully in the May or June time frame of this year. In the interest of time, let me move on we'll come back and answer any of the questions you may have here.

Then the second trial that we have underway right now is in Long COVID. And you may ask why are we looking at Long COVID and what does this have to do with Parkinson's and Alzheimer's where we have really focused for years. And the short answer is we had no idea that Long COVID was tied to Parkinson's and Alzheimer's. But first, to set the stage Long COVID symptoms are defined as persistent symptoms that last long after the COVID infection has been [indiscernible]. So many of us on this call may have been effective with COVID, after a couple of weeks or maybe longer, the body was able to mount an immune response to essentially get rid of the COVID infection. And for the vast majority of us, our lives continue, right, the infection is behind us.

But unfortunately, right now, there are at least 17 million Americans who continue to suffer the lingering effect of COVID infection, right? And it shows itself in terms of brain fog, extreme fatigue and malaise. Many of these patients cannot stay out of bed for more than a couple of hours at a time. And that's why there's more than 3 million Americans in fact, to quit their jobs or change their jobs simply because they cannot keep up with the physical demand that of the job, right? And there are no approved treatments for this. There are no treatments for Long COVID symptoms. And that's why there are these huge Long COVID centers all around the country, whereby these academic centers are just trying to provide palative or symptomatic relief for these patients because nothing works. And the situation is only getting worse. We estimate that there are tens of thousands of new patients that are getting diagnosed with Long COVID each day, right?

And how does bezisterim comes in? It comes in because it's been shown over the last couple of years that Long COVID symptoms result because there are fragments of the spike proteins and fragments of the envelope proteins continue to circulate around in the person's [indiscernible]. So while it is not infectious, the virus has been killed. So this is just a fragment of the virus that continues to circulate. But the body believes that there's still an infection. So the body is constantly mounting an immune response to the circulating protein fragments. And because of that, it generates a lot of inflammation. Inflammation works through exactly the same mechanisms where bezisterim effects. So namely ERK and NF-kappa B activation.

And because bezisterim blocks ERK and NF-kappa B activation, we believe it may become a mechanism to essentially break the cycle of information, creating more inflammation and more Long COVID symptoms. And we have been granted a $13 million grant to fully fund the Phase II trial that's currently underway. This grant allows us to enroll 200 patients half of whom will be given a placebo and then the other half will be given bezisterim. And we will follow these patients for roughly 4 months from beginning to the end. And the last patient, last visit from our Long COVID trial is expected in the back half of July which means that this trial would be in a position to read out in the August time frame of this year.

For the interest of time, let me just skip ahead -- well, let me just skip spend a few minutes ascites. Our other drug candidate is BIV201, which essentially targets and treats ascites. Ascites is end-stage liver disease. And when you get to this stage, the liver has been so scared and it creates all kinds of portal hypertension. And as a result, fluid cannot flow through the liver the way it normally does and the kidney is implicated, and therefore, the kidney cannot get rid of fluid as well. So all that fluid accumulates in your abdomen, right? So you can see that this patient has a huge amount of fluid buildup, ascites fluid build up. There is no approved treatment for ascites.

And the only thing that you can do right now is stick a large needle into the abdomen and physically remove 5 to 10 liters of that fluid. Like to get it -- procedure [indiscernible]. [ Impersonthesis ] does work. It does provide the patients with some initial belief, symptomatic relief. But since nothing has been done to address why the fluid accumulates to begin with. If fluid can reaccumulate so these patients are back in the hospital every week or 2 to get another 5 to 10 liters of fluid removed. So you can just imagine the stress and strain that this puts on to the body. And frankly, the only treatment objective at this point is to try to keep the patient alive long enough so that he or she may qualify for a liver transplant.

And since there are not enough livers to go around, [indiscernible] greater than 50% mortality rate within a year, right? And this is -- this has a huge unmet medical need. So our solution is a novel formulation of a drug called [ thromopressin ], something that's been available in Europe outside the U.S. for quite some time. It's a drug that acts as a very potent vasal constructor right? So everything your body constructs. But because of that, it has a horrible side effect profile. Our solution essentially solves that problem. So we take [ pelabresib ] and we put it into a saline bag we stick it into -- connected to a portable infusion pump that patients can wear under belt. And we slowly drip the drug in over the course of 24 hours.

So in our first Phase II trial, we showed that we were able to maintain a constant therapeutic dose of the drug by continuously dripping it in slowly over the course of the day. And by doing so, we avoid the problem of creating these massive peaks that are associated with the bolus injections, which is this the way that [ bilipessen ] is administered now, right? So in the Phase IIa, we saw no drug-related SAE or Severe Adverse Events, right? So by avoiding the peaks, we avoided the safety concerns.

Then we moved on to a Phase IIb trial where we were targeting enrolling 30 patients to try to measure how much ascites fluid buildup we can reduce. And we decided to stop the trial early halfway through after 15 patients have been enrolled because by then, we already had data showing that those that completed treatment saw a 50-plus percent reduction in [ duracites ] fluid buildup, whereas those or standard of care solve really no change.

So since this is a condition that has such high mortality, we concluded that the best thing to do, the most ethical thing to do is to stop the trial early and engage the FDA in a conversation on what it would take for us to get -- to move the drug to Phase III and registration. And since we already have fast track and order designation for this drug, all we need is one Phase III trial to register the drug. The Phase III trial for about 200 patients large. And as of now, we have received all the feedback we made from the FDA to initiate the trial, and we're exploring some things to get the funding to initiate [indiscernible] strong.

So in just a time, let me stop here by saying, in BioVie I believe we have a very, very exciting portfolio. We have 2 drug candidates in bezisterim and BIV201. So we have multiple, multiple shots on goal. Bezisterim is currently in the clinic for Parkinson's and Long COVID. The Parkinson's trial is expected to have top line data readout in the second quarter of this year. And the Long COVID trial is expected to have top line data readout by the end of the summer.

So with that, let me stop here, and let's open it up for questions.

Thanks a lot Cuong. Yes, if you wish to reach Cuong, please click on the Q&A button at the bottom of your zoom window, a text box will appear and then you will be able to type in your question.

We already have some questions already submitted. Can't COVID live for a long time in the gut and then pass spike into the system.

Frankly, we know that Long COVID last a long time. It does circulate in the blood from blood, they can go to a lot of different places. And so that's part of the reason why there has been no treatment. And we believe that we may be able to provide symptomatic relief, but there's nothing that bezisterim does that will get rid of the circulating protein fragment. So that will have to come from a different solution. But hopefully, in the meantime, we will provide a symptomatic relief, a solution for symptomatic relief for these patients, right?

And just to give you a sense of how important that is, there is absolutely nothing available for these patients out there. So if we get significant results at the end of the summer, our plan is to go to the FDA in the fall and have a conversation about what it would take to get accelerated approval or even perhaps emergency use authorization for the drug because the mercancy-use authorization is there for situations where there is a big unmet medical need, and there's nothing else that works, right? So depending on the data that we get, we will go and talk to the FDA about that.

And just to kind of give you a magnitude here. We believe that Parkinson's when fully developed could be a $3 billion to $5 billion annual sales opportunity in the U.S. alone loan. And Long COVID could be even bigger than that because of the numbers that are involved, there are 1 million Parkinson's patients in the U.S. There are 17 million Long COVID in the U.S., 3 million of whom have it very severely such that they've had to quit or change their job. So this leads to a very, very large market.

Thanks, Cuong. As a long-term investor, I have been hearing about liver ascites for quite some time. Previously, I was told BioVie was seeking a partner, what progress has been made? And when do you think you can bring this solution to the market?

That's a great question. You share my frustration with the delay in developing BIV201. We have been looking for talking with partners. Unfortunately, the partners we've been talking to has the same problem that we have, which is they are also small cap companies. So we've had significant challenges raising the $25 million that's needed to go and initiate to conduct the trial and get this drug registered. And so we are continuing to do that. But if you are a keen observer of BioVie, you may have noticed that we have also -- we are also considering taking the ascites drug public through a separate company as well. And so we're working it through with our banks and advisers and so forth. And we believe market conditions in the coming months may make it possible for us to put the ascites drug into a separate company and take that a portion of that company public to raise the funds that are needed to go and conduct that trial. So we will hope to have this drug in the clinic this year.

Thanks, Cuong. When the reverse split was initiated last year, the stock quickly fell to previous levels. Do you feel the reverse split was a good decision?

The reverse split is a terrible, a terrible thing to have to do. But unfortunately, it was the only solution that we have. We do not want to do a reverse split nor would we ever voluntarily want to go through something like that. We just had -- we faced a regulatory requirement which was our shares need to be trading about $1 in order to be maintained on the NASDAQ. And as it drifted below a dollar, the only way to get it above $1 is to do to reverse split. And our company like many, many other biotech small cap companies also have seen the exact same problem over the course of the last year, 2 years or so, which is frankly, the lack of interest. So our volume, our trading volume has also dried up as well.

So I am very frustrated with our volume, very frustrated with our share price. I do everything possible to try to get the word out about BioVie but frankly, the entire small cap biotech market is just severely depressed. And I think that's the reason why our share price has been stagnant. And believe it or not, we are in a better state than some of the other companies that we track, right? Which is not great relief, right? What we are obviously hoping for or waiting for is positive results from our 2 clinical trials and hopefully, that will give people to be more aware of what we're doing, more excited with what we're doing and they come into our stock as well.

Another question here about partnerships. How do you envision the structure for any potential partnerships? And again, have you been in any discussions with potential partners?

Over the years, we've been in discussions with a good number of partners and let me answer the question in 2 different parts. First is the question of structure, everything is on the table. Over the years, we've discussed things such as a potential partner licensing our products anywhere to potentially buying out the whole company, right? So everything is on the table regarding this got potential, right? And so we will entertain anything that makes sense for the company. And of course, there's always a question of why has it a big company [indiscernible] deal with us and so forth?

And the short answer to that comes in of the fact that in big pharma, no one has ever been fired for playing it safe. I get it, I've been on that side of the table as well. The world out there is littered with promising Phase III assets in Alzheimer's that ultimately fail and big pharma companies are just waiting for us to complete the trial to show with positive statistical significance then they will slip in, right? We know that there are big pharma companies that are monitoring us. We are continuing to have those conversations to keep the conversations warm. And what they constantly call us is going to do the trial and come back on the data. When you have positive clinical data, that's statistically significant. They want us. They want a completely derisked deal, right? And unfortunately, that just means it's -- the onus is on us to go and do the trials to show that this drug works.

Thanks, Cuong. Why wouldn't a large drug or biotech company take a chance on investing in your company?

Well, the answer is partly what I've just mentioned, which is these big pharma companies are very risk-averse, right? And no one wants to invest in a company in a field that has repeatedly failed right Alzheimer's and Parkinson have had many failures in the past. So people want to play it safe. They want now to wait for a drug that has completed Phase III clinical trials before sweeping in. And frankly, they know they will have to pay a premium. And because by then, once we have a proven drug, we then can run an auction for the drug, to run an auction for the company, and it goes to the highest bidder, right? So everyone knows that they will have to overpay worth a drug in an auction but they're willing to do that to avoid the downside risk of investing in something that fails later on.

Cuong anything happening with legal action against the testing centers in Florida whose [indiscernible] resulted in results, which did not achieve statistical significance.

That's a great question. It has been 2 years since we've had this problem. And over the course of those 2 years, we have been cooperating with the FDA and the Department of Justice and we've been working behind the scenes to urge them to move more quickly. What we know is that the FDA has inspectors out to, I believe, 2 handful of the 15 sites that we reported to them. They have set inspectors out. And there have been a number of what I call 483 site patients, I think that's the number, whereby essentially saying that these sites did not adhere to the protocol did not do things correctly. And as well, there's been a few other kinds of reports and filings that the FDA has put in for many of the sites that they have visited.

What we have been waiting for is for them to initiate a criminal prosecution. We believe a criminal investigation is underway. We will give it a little bit more time, right? And if the FDA of the DOJ does not initiate the next set of litigation we may initiate a litigation ourselves because part of the reason why we wanted to wait and cooperate with the FDA is that they have far more investigative powers than we do, right? And they -- what they do is, frankly, free to us, we do not have to pay money for various investigators and people who go out to the sites and so forth.

And more importantly, they have [indiscernible] power. And we know that the reports at the FDA have sent back to the sites. We get a copy of those through our contracts with the site base if we make it very clear that the sites that received those reports did not follow what they were supposed to, i.e., they're at fault. So we will give it a little bit more time because if the FDA initiate litigation, it will make it easier for us just to jump on their [indiscernible]. But if -- they do not do something within the coming months, we may choose to initiate the litigation ourselves. Hopefully, that explains the question. Thank you for the question.

Cuong this may be a good time to remind everyone that you have prior experience at Merck and Samsung and this person wants to know, given that prior experience, what lessons, including partnerships would you be applying to BioVie's overall strategy?

That's a very broad and big question, right? What I know in my 3 decades of developing drugs. Is that a company is valued based on its track. If you have a drug, especially if you have a drug that's in Phase III or a completed Phase III, that's when the big value inflection comes in. It's point -- it's lesson number one. Lesson number two is data from these trials becomes the catalyst whereby different companies get noticed, not only by investors by potential licensors or acquirers. And if we're able to get more than 2, more than 1, right? So if we get 2 companies that are potentially interested in our asset or our company you have a bidding situation. And when you have a bidding situation for a drug where there are a few alternatives, it very quickly leads to a bidding frenzy I've seen that over and over and over again.

And obviously, that's what we are working to create here at BioVie so that we can get the drug into the hands of the best and the most logical owner because they want have more resources, they can develop a drug and get it off with the patients. And by doing so, going through that process, that would generate significant returns for our shareholders who have been backing us well all this time.

This person writes pardon my ignorance is the top line data for Parkinson's and Long COVID later this year, Phase II results?

I believe the answer to that is, yes. Both our Parkinson's and Long COVID trials are Phase II trials whereby we are trying to demonstrate the magnitude of the impact of the drug. And to a certain extent, safety, although we've already demonstrated safety, we've never seen a safety concern. So while I do not make light of any safety observations, we believe that we have shown bezisterim to be safe. What we need to do now is to show the magnitude of the therapeutic impact that bezisterim has in Parkinson's and in Long COVID.

What that means is we want to measure how much improvement can bezisterim treated patients, experience compared to those who were treated with placebo. And by understanding that different. We then can go and use a standard statistical model to estimate and to determine how many patients do we need to have in the Phase III trial so that we can get the positive results and statistical significance that will be required for us to go and register the drug with the FDA. I hope that's clear.

I certainly think so. So thank you very much Cuong. We've got a few here to choose from. Let's get one about bezisterim here. As you said, you are addressing with bezisterim, Alzheimer's, Parkinson's and Long COVID and longevity. And what is the priority there? What's the hierarchy there looking like strategically?

Number one priority is Parkinson's. Number two priority is Long COVID with [ 1 proviso ]. If we get very strong results and the FDA is willing to give us clear guidance on accelerated approval or emergency use for Long COVID, that becomes the #1 priority. So that -- those 2, the data will tell and frankly, the FDA's reaction will tell. Long COVID is the big wild card because it's the first drug of its kind and we just don't know how the FDA is going to react. Whereas Parkinson's, is the first new drug in Parkinson's in over 5 decades and the registration path, the clinical trials and so forth is fairly clear.

And let me give some guidance. I believe there's a question about how long it will take. So we make you some timing guidance as well. But when we get the positive Phase II data from Parkinson's, it doesn't mean that we can turn right around and start the Phase III trial right away. From Phase II data until such time as we can start the trial, it could take at least 6 to 9 months time for us to plan the Phase III trials to get the clinical sites up and running to raise the funding for the trial and so forth. So it could be 6 to 9 months between second quarter of this year, when we get results until such time as we can start the Phase III.

Once we start the Phase III, we expect that we can have the top line data for the -- for the easy indication, just symptomatic relief, we can have the top line data within 1 year, right, for symptomatic relief. But we will continue that trial probably for another year beyond that so that we can demonstrate that we can help the patients modify the progression of their disease right? So the ultimate trial will last longer, but that's when we get the final ultimate trial, that's where the true value comes in because if we're able to demonstrate, but the first time that a drug can modify the progression of disease. That's the holy grail. I hope that answers your question.

Okay. Well, we have reached -- we're even beyond the 5:00 hour here at Eastern Time. Cuong wrap up here, and we appreciate you taking the time to do today's webinar. For more information...

Thank you, Craig. Thank you, everyone, for joining today. Let me just reiterate and recap that at BioVie, we have 2 drug candidates in bezisterim and BIV201. I believe we have a very exciting portfolio in these 2 drugs that are being developed for multiple different indications. Of course, bezisterim is being developed for Parkinson's, Long COVID and Alzheimer's. Our Parkinson's trial is currently underway, top line data is expected second quarter of this year and when fully developed, Parkinson's could become a $3 billion to $5 billion annual sales opportunity in the U.S. alone.

The Long COVID trial is expected to read out at the end of the summer. And if it could become the first therapy for Long COVID and when fully developed, that could cross the Parkinson's market size opportunity, just given the need -- the significant need that's there.

And in [indiscernible] or BIV201, we've received all the feedback that we need from the FDA to initiate or to move into the next stage, us getting this thing into the Phase III clinical trial. And when developed, this could become the first therapy for ascites, which is a condition that has greater than 50% mortality rate within 12 months. At this, we believe, can become a $2 billion annual cell drug in U.S. alone.

So I thank you very much for your time. And if you're interested in more information about us, please go to bioviepharma.com and that's spelled bioviepharma.com for more information about the company and our clinical trials.

Thank you so much for your time. You have a great day.

Thank you Cuong. And just a bit more information. There's another page you can go to. Certainly, you can go to the page that Cuong just gave you. RedChip has a Page too biviinfo.com that can also lead to BioVie corporate page. But when you're on biviiinfo.com, you can also sign up for news alerts on BioVie. You can read the investor presentation. as, of course, you can also do on the corporate website.

We also have a fact sheet that we create exclusively for BioVie on that web page, you can download it very easily. You can also reach us if you want more information on BioVie at [email protected]. Of course, you can always call us at 1800 RedChip. Please watch small stocks big money, RedChip's program featuring exciting small cap companies, including, of course, occasionally BioVie every Saturday night at 7:00 p.m. Eastern on Bloomberg USA.

And finally, please join our next webinar with Jackpot Digital that will be tomorrow at 4:15 p.m. U.S. Eastern. Just like today, register for all RedChip webinars at redchip.com/events. Thanks again to our many participants today. And as always, thank you so much, Cuong.

Thank you, everyone. Have a good day.

Hello, everyone, and welcome. This is Paul Kuntz with RedChip Companies. I want to thank everyone for joining today's event with BioVie. BioVie trades on the NASDAQ under the ticker BIVI. With us today, we have Cuong Do, President and CEO of BioVie.

We will begin with a brief presentation in a moment and then we open up the event for your questions. You can submit your questions at any time by using the Q&A tool at the bottom of the Zoom window.

Before we begin, please allow me to read the safe harbor statement. This call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements pertaining to future financial and/or operating results, along with other statements about the future expectations, beliefs, goals, plans or prospects expressed by management constitute forward-looking statements. Any statements that are not historical facts should also be considered forward-looking and, of course, forward-looking statements involve risks and uncertainties.

With that, I will now turn the webinar over to BioVie's President and CEO, Cuong Do. Please go ahead.

Thank you, Paul. Thank you, everyone, for joining today and good afternoon. I'd like to give us an update and a bit of a recap of where we stand over the course of the year. Just a reminder, we have 2 assets in the company. Our lead asset is a drug called bezisterim, formerly known as NE3107. It is a novel inhibitor of TNF alpha and in clinical trials that's been shown to be able to reduce inflammation and the associated insulin resistance. Our Parkinson's patients have seen improved muscle control in our earlier Phase II trial. Alzheimer's patients have experienced a 68% slowing of cognitive decline after just 6 months of treatment, and everyone has experienced lower levels of DNA methylation, essentially a modulation of the biological aging process. We can go into some of this later as part of the Q&A, if you like.

Our second drug candidate that we don't spend enough time discussing is BIV201. This is essentially the origins to company. This drug is being developed for ascites, which is late-stage end-stage liver disease. It's a condition that have over 50% mortality rate within 12 months, right? So it's a horrible condition, then we'll spend a little bit of time discussing today.

Before we go into each one of these, I'd like to give a bit of a status update, so a timing update and outlook for what to expect over the course of next year. First is our Parkinson's trial. We are currently conducting a Phase IIb in Parkinson's, as you know, and we'll go into greater detail on that program in a minute. But the update is that program is now almost fully enrolled. We are almost complete with enrollment and we expect a full enrollment by the end of this year. And this is a 3-month treatment duration trial, which puts us in a position to expect to have top line data readout in May 2026.

So Parkinson's is nearly fully enrolled, we expect full enrollment by the end of the year, top line data readout in 2026. In addition, we are currently conducting a Long COVID trial. Enrollment in this trial is accelerating. As of now, almost all of our clinical sites are fully up and running and active. I believe that only one academic site is still in the late stages of getting ready. We expect full enrollment of this trial in late February. And as such, we expect top line data readout in summer of 2026. As the trial proceeds, we accumulate -- we monitor what's going on with the subjects on a daily, weekly basis. First off, we have to monitor for safety, just to make sure that there's nothing crazy that's going on. And there's been no safety concerns in what we see so far.

So blinded data is accumulating on a daily basis. And we would expect to have sufficient blinded data in late first quarter to be able to start to see if there are any patterns on the efficacy side of the equation. And what we're hoping to see, of course, is a spreading, a spread to start to develop, right? We hope to see that those -- a group of people who are getting better and then there's a different group of people who are getting worse or not improving. If there's a beginning to be of a spread, that starts to give us a signal that the drug may be doing something and that may give us a sense of what to expect when the data becomes fully unblinded, right?

I underscore May here because when data is blinded, there are still many things that could go wrong, right? But if there's no spreading patterns and so forth, that gives us a different thing to start thinking about versus when there's a spread in the pattern of the data that we start to see.

And lastly, on our ascites program, you may recall that we terminated the trial early so that we can engage the FDA in a conversation on what it would take to move to Phase III and register the trial. As of now, we have received all feedback that we need to move into Phase III from the FDA. And since we already have orphan and fast-track designation, we only need one Phase III trial to be completed and to register the drug. And that's up now. We are exploring partnering and other funding options that we hope to give a further update in the first half of next year, right? So that's the quick update. Now let's go into deeper a bit.

As you know, we believe that inflammation is the root of all things that start to go wrong in the body, and it really starts with TNF alpha. TNF alpha is considered to be the master regulator of inflammation. When you have TNF alpha it drives the release of a bunch of cytokines, chemokines and other things that leads to a pro inflammatory inflammation cycle, which has been implicated by a number of these diseases that you see here, right?

And once you have TNF alpha and inflammation, it drives something called IKK and JNK, which leads to insulin resistance, which, of course, is associated, implicated in diabetes, metabolic diseases and Parkinson's. We'll come back and discuss Parkinson much more, right? TNF alpha draw also drives something called DNA methyltransferases 3A and B which drives DNA methylation, which essentially is playing with the biological aging process. And it turns out that our drug candidate affects inflammation in just the central node and involving ERK and NF-kappa B.

It's been known for decades now that ERK plays 2 very different roles in virtually every cell in our body. The first involves insulin signaling. Insulin goes through a series of steps involving insulin substrate receptor 1 and 2 IRS 1 and 2, and eventually activates ERK for all of its cellular growth repair and regeneration activities. This is known as homeostatic ERK. But ERK is also involved in inflammation, right? So different extracellular signals such as cytokines, chemokines, who enter the body will activate MEK and activate ERK. When ERK is activated, which then that incurs activate NF-kappa B and triggers the production of TNF alpha. When you have TNF alpha, it creates a forward-feeding pro inflammatory cycle that leads to more inflammation.

So it's obvious what you want to do. You want to block inflammatory ERK, but not touch homeostatic ERK. Unfortunately, that is much easier said than done because dozens of teams have tried over the years, but they all failed. All of those drug candidates failed due to toxicity because no one was able to create a selective enough inhibitor of just inflammatory ERK. It was touching insulin signaling as well. And whenever you touch insulin signaling, you're going to create toxicity problem. And that's where bezisterim comes in, right? And to be frank, we did not set out to do this. We got lucky, right? We just had our eyes open when we observed this effect.

It turns out that bezisterim blocks the activation of ERK and NF-kappa B, as you can see here. And when you block the activation of NF-kappa B and ERK, you do not have the production of TNF alpha, right? And when you do not have TNF alpha, you do not have insulin resistance, right? As I mentioned before, insulin resistance is triggered by TNF-alpha, activating ERK and NF-kappa B. It is triggered by the insulin substrate receptor 1 and 2. It turns out that naturally insulin binds insulin substrate receptor 1 and 2 on a tyrosine residue, which then goes through this natural process here. But when you have inflammation, JNK and NF-kappa B also activate and it binds to the IRS 1 and 2 on the serine residue, right?

So when the serine residue is activated and occupied, it blocks the tyrosine site and insulin is not then able to bind into the tyrosine site. And that's how you have insulin resistance, right? It's inflammation, activating JNK and IKK, activating the serene site and IRS 1 and 2, which then creates insulin resistance. And by bezisterim's ability to block NF-kappa B and thus the production of TNF alpha, it's believed that we're actually alleviating the activation of JNK and IKK. We're opening up -- we're freeing up the serine site, opening up the tyrosine cytokine.

So I know that's a lot of science and a lot of mechanism there, but that's critical to understand how the drug works. And I have to first turn to Parkinson's. Two things need to be true at the same time for a person to develop Parkinson's symptoms. And this has been known for decades. The first is that you need to have low dopamine levels in the brain and then the second is you need neuro inflammation and the associated insulin resistance in the brain. If you're somehow able to reverse the insulin resistance in the brain, the brain is then able to make use of whatever level of dopamine that's there and help to restore muscle control.

So people have tried for a long time and tried lots of different ways, lots of crazy things as well to try to reverse insulin resistance in the brain, including this study, which used inhaled insulin just to try to get more insulin through the nose up into the brain so that you can free up more glucose. And it works. If you're able to get enough inhaled insulin up into the brain, you create more glucose and the brain then is able to make use of the dopamine that's there. That's what you see here. But of course, that's not a very practical thing -- solution to use, right. Inhaled insulin to treat Parkinson's. It's not a very recognized solution. And nothing else has been very practical.

And as a result, the drug levodopa remains the standard of care for treating Parkinson's over 5 decades after it was introduced, right? Now levodopa is a great drug. It is a really, really good drug in restoring muscle control, and that's why it remains a standard of care. But there are a few problems associated with levodopa. The first is that it has a short half-life. Such that Parkinson's patients end up having to take it every 3, 4 hours or so which then becomes a real problem overnight when you go to sleep, right. When you go to sleep, levodopa wears off, so that in the morning, you're rigid, your muscle is rigid, you can't get out of bed. So that's one problem associated with levodopa.

The second is that the effect of the drug wanes over time. So the longer you take the drug, the higher the dose you need to have just to get that effect. But as you get into higher and higher doses because of something called levodopa-induced dyskinesia, which is the tremors that you see many Parkinson's patients have. And when you have the dyskinesia, all you can do is to cut back on the levodopa dose and wait for the dyskinesia to pass. But as you cut back on the levodopa, you lose muscle control and you are rigid, right? So it's a terrible, terrible situation that Parkinson's patients have faced, right? And that's why that we believe that bezisterim may play a role in addressing this problem.

In our preclinical research, we found that in mice and rodents, and in nonhuman primates, in monkeys. We found that bezisterim was equally effective as restoring muscle control as bezisterim. Now that is a huge statement right? Because over the decades, nothing has been able to equal levodopa in its restoration of muscle control. But here, we found that bezisterim alone was equally effective as levodopa in restoring muscle control in rodents and in monkeys. And what we also found is when you use it in combination, when you give bezisterim in the combination of levodopa, you saw a synergistic effect. We saw a significant -- a statistically significant improvement in muscle control when used in combination, right?

So this is a disease score, so a lower score is better. The other thing we found is that when we use it in combination, we saw a reduction of dyskinesia. This is a very complicated chart to read, right? So when those monkeys that were given a placebo and levodopa right? So levodopa alone, as shown in the thin green line here, you see many abnormal involuntary movements. So very many tremors, right? So the distribution skews to the right, but when you give bezisterim and levodopa, you see that the distribution skews all the way to the left. It dramatically reduced the incidence of dyskinesia.

And what got most people, all of us, very excited is that at the end of the study when we sacrificed the monkeys and looked at their brains. We found that those that were treated with bezisterim retained twice as many dopaminergic neurons as those that were in control, suggesting that there is a neuroprotective property to the drug. And this to us is not at all surprising, right? Because we know that bezisterim reverses insulin resistance, which means that there is greater glucose availability in the brain.

We also know from various imaging studies and other ways that bezisterim enhances blood flow to the brain, which means there's greater oxygen availability in the brain. So when you have greater oxygen and glucose availability, it only bodes well for better neuronal health, right? So this was terrific work that, frankly, we were pointed in this direction by funding that was provided by the Michael J. Fox Foundation. So we're grateful to them and they continue to help us for our trial today.

So based upon this research, we wanted to go into the clinic. And so we enrolled 40 moderate-to-severe Parkinson's patients and essentially replicated in human patients, a study that we did in monkeys, right? So what we did is we gave half the patients placebo and levodopa, essentially just levodopa alone, as shown in red here. And we get the other half, bezisterim and levodopa. So the combination is shown in blue. And after 28 days of treatment, we saw that those that we treated with the combination experienced a greater than 3-point advantage on the Part III score or the muscle or motor score of unified Parkinson's disease rating scale.

Now that's a clinically meaningful difference. But if you look at patients who are younger than 70 years old, which is about half the population that was in this trial, that difference was somewhere between 4 and 5 points. Now that's a big difference that you do not see very often. But the other thing that was very terrific to see has to do what's called the morning on symptoms. As I mentioned before, levodopa wears off overnight. So this happens every day in life and have been in this trial. In this trial, patients would come into our sites, they would take their evening medications and go to bed. And then first thing in the morning before they take their morning medication, we would measure the muscle control again. And what we found is that none of the patients that were given to placebo and levodopa, so just levodopa alone. None of those patients have their muscles in the on state, none of them could move, none of them could get out of bed.

So their muscles were considered to be in the off-state, but about 1/3 of the patients that were given the combination of bezisterim and levodopa had their muscles in the on state, right? And this was an unexpected statistically significant finding, right? This was a small trial, so we did not expect statistical significance on this, but we had statistical significance, partly all driven despite the magnitude of the impact that bezisterim has. So this gives us human proof of concept that you can use bezisterim and levodopa to help moderate and severe Parkinson's patients improve their muscle control, and it establishes the first half of what we want to show in Parkinson's.

We are -- right, which is you can use bezisterim and levodopa in combination to help moderate-to-severe Parkinson's patients. We are now embarked in the middle of another trial to establish the second half of what we want to show, which is bezisterim can be used as monotherapy. So it can be used alone earlier in the disease progression, right? So we are now enrolling 60 patients in a trial of Parkinson's patients who needs to go on to treatment for the first time to treat their disease symptoms. Half of patients will be enrolled, it will be randomized to placebo, and then the other half will be randomized to just bezisterim alone. This trial will run for 3 months and what we're hoping to show is that those patients that are treated with bezisterim will have a slowing of their loss of muscle control, right? Whereas we believe that those on placebo will have greater muscle loss -- motor control loss, right?

And the other thing is that we expect -- we think what may happen is that a greater proportion of patients that are in the placebo arm may need to drop out of the study as well so that they can go on to levodopa, right? This is a short and small study. It is only 3 months long. It's only 60 patients large. In many ways, we do not expect to see statistical significance in the Part III score here because it's an exploratory study. And what we're hoping to see is the magnitude of the impact at the Part III score so that we can power the Phase III study. But we are fairly confident that when we'll see statistically significant changes in many of the component pieces that lead that contribute to the Part II score, the Part III score and the various other endpoints that we are doing.

So this trial is almost fully enrolled, right? And we expect this to be fully enrolled by the end of the year. We expect to have data coming out of this trial in the May time frame of next year that would allow us to power the 2 Phase III trials that we would expect to run. The Phase III program will have 2 parts to it. The first part would demonstrate symptomatic relief, right? So that would be a short 3, possibly 6-month study to demonstrate that we could give symptomatic relief to new, to patients who need to go on to therapy for the first time. But we will continue to follow these patients in an open-label study for another year in anticipation of demonstrating disease modification, right?

And when taken in totality, we believe that this would allow bezisterim hopefully to become the first newly -- the first new therapy for Parkinson's patients in over 5 decades. The first new therapy that would be able to restore muscle function in a manner that's equal to or better than levodopa, and also could be used in combination with levodopa for more severe patients in the disease -- with the disease. When fully developed, we believe this could represent a $3 billion to $5 billion annual sales opportunity in the United States alone, right.

With that, let me move on to our work in Long COVID, right? And you may think and ask the question, why Long COVID, what does Long COVID have to do with Alzheimer's and Parkinson's. And the short answer is really very little, except the mechanism of action, and it's also CNS related. Long COVID is defined as having persistent symptoms, at least 3 months after the infection has been beaten, but many of us have moved on. The world has moved on, believing that Long COVID -- believing that COVID has been beaten. It's behind us. But the reality is thousands of patients are still getting infected with COVID every single day in the U.S. right now, right? And 17 million Americans are currently suffering from Long COVID symptoms, primarily brain fog, fatigue and malaise. And roughly 3 million of these Americans have the conditions so severely that they have had to quit or change their job simply because they can no longer keep up with the physical demands of the job, right?

There are people who have difficulty staying out of bed for more than 2 or 3 hours, right? Or people who just cannot focus and have the cognitive function that they used to, right, 3 million. And this is part of the reason why there are so many large Long COVID centers out there, particularly at academic medical sites, right? We did not know any of this, right, until some of the experts we were working with turned us on to it, right? We were really focused on Alzheimer's and Parkinson's. But what the experts really turned us on to is that within the last couple of years, researchers have tied Long COVID symptoms to inflammation. And it's really working through 2 things: the spike protein and the envelope proteins.

What happens is that for these 17 million and perhaps even more Americans even after we have beaten the infection, you could have fragments of the spike protein and the envelope protein continuing to circulate around in your bloodstream, in your body. And as a result, the body's immune system believes that there's still an infection. So it's constantly mounting an immune response. And as such, it's creating inflammation, okay?

Because the spike protein is working through the pathway TLR4 or toll-like receptor 4 and then the envelope protein is working TLR2, both TLR2 and 4 is a couple of steps upstream from the activation of ERK and NF-kappa B. And that's the reason why we and many other experts out there believe that there's good reason to believe that bezisterim may be able to block the activation and the production of TNF alpha and block inflammation for these patients.

We were made about known -- we were alerted to this by our experts. And they also told us of the various grant programs that were available out there. So we applied for a grant and we were given a $13 million grant to fully fund an exploratory trial in Long COVID, right? This grant allows us to enroll over 200 patients. Half of the patients will be given placebo and the other half will be given bezisterim twice a day. And as of now, this trial is enrolling very rapidly. Acceleration -- the enrollment is accelerating. We have one academic site that is still in the final stages of getting activated. And as such, we expect this to be fully enrolled by the end of February, which puts us in a position to have top line data readout in the summer time frame.

To be fully transparent, we do not know what to expect in this trial. We have no preclinical studies to give us a hint. There are no preclinical models of Long COVID that's reliable in this arena. So we do not know what to expect. But mechanistically, we know that this makes sense. But the other thing that we do know is that there are a good number of patients out there who do not qualify for this trial. For example, you may not qualify because of the age, right? And you may not live near one of our sites. So over the years, we also have had -- we have also supported something called investigator-initiated trials. Where we would support various researchers who may have a plausible theory as to how bezisterim may contribute to addressing a need that their patient may have. And as such, we have supported trials in traumatic brain injury, ALS and so forth.

We've had some researchers come to us asking for support for their patients in Long COVID. So we've had several patients supported through this. And through those IITs, all the patients have gotten better, right? All the patients in these investigator-initiated trials have gotten better in their cognition and their malaise and fatigue. We know of 1 patient who frankly was just not able to stay up for more than 2 to 3 hours at a time. This was a very accomplished person who was older in age, but thus could not qualify for a trial. And just could not stay up and rarely left his house. He got so well that he was able to go on vacation this past summer, right? And we basically -- he and his clinician are very happy with his progress. His various endpoints, the scores that we measure in this, it's all improving, and his clinician is preparing a case study right now that we hope to publish relatively soon, just to tell the world on how this one particular patient is improving, right?

So that is a sample of one. But if that sample, coupled with some of the blind data -- blinded data that we're beginning to see in this trial continues to develop the way that we think it would develop. We believe that there's a very good chance that we may see statistically significant improvement for patients in either fatigue and/or brain fog. So we're looking at all combinations of fatigue alone, cognitive functions alone or the combination of the two. And if should we see that results, statistically significant result in either of those -- in any of those combinations. One thing that we're working towards right now is a conversation with the FDA sometime later next year about an emergency use authorization for an accelerated approval. Because there are many, many patients out there, 13 million -- 17 million patients affected, 3 million very severely.

So the unmet medical need is very high. There are no approved therapy for this condition. So patients really have nothing to help them, right? And that's why the emergency use pathway is there, right? And we are eagerly working and eyeing that pathway as a possibility of what may unfold next year as we unblind the study next summer. So with that, let me stop here and be mindful of time, let me move very quickly on to ascites, which is end-stage liver disease. Ascites is condition that you get to when the liver has been very, very scarred. By this point, you've gone through fibrosis, cirrhosis and so forth and the liver has been so scarred that it is no longer able to process fluid the way it normally does. And the kidney is also implicated at this point in time. So as such, fluid accumulates in the abdomen, right? And since there's no therapy for this, the only solution is to stick a large needle into the abdomen and physically remove the fluid, right?

And since nothing has been done to address why the fluid accumulates in the first place. These patients are back in the emergency room at the hospital every 1 or 2 weeks to get another 5 to 10 liters of fluid removed. So you can just imagine the strain that this puts on to the body. This is just not water, right? This is -- think of it as serum, so there's protein. There's lots of other things that are in, nutrients that are in this fluid. So these patients end up being malnourished and many other things, right? And so frankly, the only treatment objective at this point in time is to try to keep the patient alive for as long as possible so that they may qualify for a liver transplant. And since there are not enough liver transplant to go around the mortality rate in this condition is over 50% in 12 months.

So it's a horrible condition where there's no current therapy. We believe that our drug candidate, BIV201 may be that first therapy. It is a novel formulation of a drug called terlipressin. Terlipressin is a very, very potent vasal constructor that was first approved in Europe in the mid-80s, right? It's -- first of all, it's a peptide. So it has to be refrigerated. It's very potent. So you only need 2 milligrams of this drug. So how it works is that you would measure 2 milligrams and put it into an IV bolus and you give it to the patient, which then causes a severe constriction of virtually all the blood vessels in your body. And this was first approved to treat a condition called bleeding esophageal varices, which is a complication from ascites, whereby the patient is just bleeding out, right?

So terlipressin represents the last chance a clinician has to try to stop the bleeding and prevent the patient from bleeding out, and you would use it despite the fact that this creates a big blood spike of the drug, which then creates all kinds of side effects. You'll put up with side effects if you can try to keep the patient alive. So this has been used abroad for a very long time. So we know that the drug works. But it was not approved in the U.S. up until very recently because of this dramatic severe side effect, right?

And what we do instead is we take the same 2-milligram. Through a novel formulation, we're able to put it into a continuous infusion pump, keep it and use it at room temperature instead of having to be refrigerated. We can use that at room temperature, cook it up to a portable infusion pump and drip it into patients slowly over the course of the day. We conducted a Phase IIa starting to evaluate safety, and we found no drug-related safety concerns. We then moved on to a Phase IIb trial to try to measure the magnitude of therapeutic impact here. So how much can we actually affect the efficacy side?

We intended to enroll 30 patients, but after just 15 patients, we already had statistically significant data to show that those completing treatment saw a 50-plus percent reduction worth of ascites fluid, with just the treatment. Whereas those on standard of care saw no change, right? And in fact, one patient did not have to go back for another paracentesis, right? And since the mortality rate is so high here, we concluded that the only ethical thing for us to do as a company is to stop the study early and to engage the FDA in a conversation to see what it would take for us to go into Phase III trial to get this drug registered. And since we already have orphan and fast track designation, we only need to complete 1 Phase III trial to get this registered.

As of now, we have received all the feedback we need from the FDA to proceed with this program, right? And we are in conversations and exploring various partnering and other funding opportunities to launch this program. We hope to give a further update in the first half of next year as to when this program could be launched. And from funding, from the moment we have funding, we believe this drug could be on the market in as short as 3 years, right, because we only have one trial to conduct. But this is a complicated trial.

This will be a global trial that will be led out of Europe by our principal investigator out of Italy, who is the most experienced person in this field. All right. So let me just stop here and summarize. BioVie has 2 drug candidates. Bezisterim is currently in the clinic for Parkinson's and Long COVID. The Parkinson's trial is expected to be fully enrolled by the end of this calendar year. As such, we expect to have top line data readout by May of 2026. Our Long COVID trial is currently enrolling. We expect that to be fully enrolled by the end of February, which puts us in a position to have top line data readout by the summertime. And in addition to that, our liver disease program or ascites program has received all the feedback we need from the FDA to proceed. We are now exploring funding options, and we hope to start that program sometime next year, and we'll give additional feedback and update in early part of -- the first half of next year.

With that, and being mindful of time, let me open it up for any questions that you may have. Thank you very much.

Great. Thank you for a great presentation, Cuong, as always. We are, as Cuong just said, going to open up the event for questions. [Operator Instructions] What company manufactures levodopa?

Levodopa is currently a generic drug. It has been on the market for quite some time, right? So that is generic. Many manufacturers make it.

And our next question, how can somebody in Virginia get into the Parkinson's study?

It may be too late right now. But the Parkinson's trial actually has a very innovative design and a very unique design, whereby we send patient -- nurses out to see the patients. One thing you should know is that Parkinson's is actually a very difficult trial to conduct because by the mere fact that a person is going into a clinical site, that person thinks that he or she is going to get better treatment, and that may trigger a placebo effect, right? And many trials have failed or have seen less stellar results simply because of this placebo effect.

To avoid that placebo effect, we did 2 things in the innovative design for current trial. One of those is that we send patients out to their homes. So that we can actually keep everything as constant and as stable as possible. And when the nurse goes out to the house, everything is videoed, right? And all the videos, both from the in-home visits as well as those from our in site visits are then centrally rated by a team of 3 expert reviewers. That way, we try to keep everything constant for the patient, and we keep everything consistent across all the sites, all the patients because we have the same 3 people reviewing. I give that context because you can go to our website, there's a place that you can contact.

You can put in a contact to see if you may qualify. And if you qualify, we can send a nurse out to your home in Virginia or anywhere else in a contiguous 48 states in the U.S. But as I said, we are very close to full enrollment right now. So you need to hurry and there's no guarantee that there's still time to qualify for the trial. Hopefully, that answered your question.

And our next question, do you think you have an open-label extension on the current Phase II Parkinson study?

We are currently not planning on an open-label extension. But again, in the design of the trial, we do have a data monitoring committee that is unblinded to the data as we go along. And it may be very possible for any number of reasons that data monitoring committee may come back to us and may recommend doing an open-label extension of the trial, particularly if there is -- if the patients are getting benefit from a treatment, it would be a shame to discontinue treatment that those patients are benefiting. So we may consider an open label, but that really depends on the data monitoring committee.

Thanks, Cuong. And couple of related questions there. Are any Alzheimer's trials under consideration? And where does the Alzheimer's program fit with the Parkinson's trial.

The Alzheimer's program right now is on hold. You may recall that we conducted an Alzheimer's trial a couple of years back and when we unblinded the data, we found that those treated with bezisterim for 6 months saw a 68% slowing of cognitive decline compared to placebo, right? And the #1 reported safety concern was a mild headache reported by fewer than 8% of patients, right? And that mild headache disappeared after a day. And to give you context between those -- for those numbers. You may also note that there are 2 drugs currently on the market to treat Alzheimer's. These are known as antibodies to the amyloid plaques. And as a class, these drugs have been able to demonstrate a 30% slowing of cognitive decline after 18 months of treatment. And that's part of the reason why clinicians question whether or not there's a real therapeutic benefit at all with these drugs, 30% slowing of cognitive decline after 18 months of treatment compared to bezisterim slowing of 68% of slowing of cognitive decline after just 6 months of treatment.

In addition, the monoclonals have significant concerns about safety. Particularly around brain swelling and brain bleeding. And that's why these patients have to be monitored by PET scans. Now I get these numbers, not to mean, not to imply a head-to-head comparison has been conducted. No head-to-head comparison has been conducted. These are just results that have been reported by various studies out there, right, that they are the best that we can have at this point in time to try to draw any kind of comparative -- comparisons. But the problem we ran into then is that we had a problem whereby we had to exclude patients from 15 clinical sites who did not properly follow a protocol. And by excluding those patients, we missed our statistical significance, right?

We are convinced that drug works, but we just missed on statistical significance 2 years ago. So we have every intention of redoing that trial. So what we are doing now is waiting until such time as funding becomes available and we will restart the trial at that point in time. Funding could come from a partner, but it could come from when we have positive results from Parkinson's and Long COVID that may create a catalyst for us to go and raise some additional funding as well. Hopefully, that answered your question.

Thanks, Cuong. And next question, have you had any discussions about partnering with a large pharma company to help fund more accelerated trials?

That's a great question. We've had a good number of conversations with big pharma companies, larger -- big pharma, right? And we know that a number of them are very intrigued with this mechanism and they're waiting for data. They were waiting for the data that we hope to have had 2 years ago. And when we missed on statistical stats, they basically wished us well, urged us to redo the study, and they'll be waiting for us when the data completes.

And I get it. I've been on their side of this table, right? The world out there is littered with promising molecules in Alzheimer's that failed in Phase III. And in big pharma, no one has ever been fired for playing it safe. You only can get fired for playing -- for essentially going out on a limb and losing, right? So that's why big pharma like to play it safe. And they eventually will overpay and so forth, but that's okay. So it's really -- the onus is now on us to go and do the Phase III in Alzheimer's. If we get positive statistically significant data from this Phase II trial, there may be an opportunity for engagement with big pharma, but more likely, we'll probably need to go and do the phase III trial in Parkinson's ourselves as well.

But if we get statistically significant data in Long COVID and guidance from the FDA for how -- for emergency authorization, I think, that is we will be high target for a takeout or a partnering conversation at that point in time.

And our next question, given the changes at the FDA, are you concerned that there will be any delays in obtaining the approvals you need to move forward?

That is always the risk, right? But maybe we are experiencing an anomaly or frankly, what we are experiencing may not be the kind of stuff that makes headlines. But what we're experiencing right now is timely engagement with the FDA. We have not seen any meaningful delays in our conversations with the FDA on the trials that we are conducting or have been in discussions with them, right? So we're hopeful that, that will keep up.

Thank you, Cuong. And back to the previous Alzheimer's drug trial, did you ever take legal action against the testing centers that disrupted the trial?

Great question. This actually ties into the conversation about funding for Alzheimer's drugs. All -- many investors have asked me to basically unleash the lawyers, go after the 15 sites and get compensation that could be used to help support the next Alzheimer's trial. And we will do that. We have not done it so far. The approach that we have taken is to support the FDA and the DOJ, the Department of Justice in investigating these sites. We know that the FDA has set up investigators to the sites that have been the most active enrollers of patients in our trials. We know that the FDA has been handing out 483 citations, which basically says that you failed to adhere to the protocol and did not conduct a trial in the, right? And we're just waiting for them to take the appropriate next step and render their findings.

Because the -- they have far more investigative power than we do. So we'll give them a little bit more time in hopes that they will make their findings public at such time, we will initiate our steps, but we only have so much patients. So we will rethink how long we wait for the FDA and we'll give you more guidance on that over the course of the first half of next year.

Thank you, Cuong. And I think we have somebody with their hand raised. We'll get to you in one moment. Another question we had. You've been talking to major pharma companies for the liver ascites drug for quite some time. Why have there not been any takers?

Great question. I wish I had a good answer to that, too. There is one midsized pharma company that is the most logical partner for us to work with on this program. But unfortunately, they have been held up by their own internal changes, management changes, mergers and so forth. But luckily, that is now behind them. And hopefully, management is able to focus a bit more on some other things beyond the internal challenges. We know that the scientists in those -- in that company really likes this program. We've been in discussion with the scientists for years, and they really want to work with us, but they have never been able to get this thing up and get the attention and support of management.

And now that, that is behind us. We're hoping to essentially get this elevated in management to initiate those conversations. The companies that have shown much greater interest, unfortunately, are smaller companies. And they, like us, have had to go through a very difficult fundraising environment, right? And we need to raise $25 million to really initiate this next phase. And for small companies, raising $25 million to supportive program that you're going to partner on has been a tall order, and that's the reason why all these companies have been trying to raise the funds and have not been able to raise the funds to come back to us to initiate this program.

Thank you, Cuong. And we're going to go to Mike, you can help me here to let -- [ Mike Samuels ], you have a question here.

Cuong, a quick question. In the past couple of years, we've been doing these tests. We've had multiple reverse splits, multiple money raising. Currently, do we have enough funds on hand to get us through how far?

Yes, great question. Thanks for that. As of now, we have sufficient cash to go to 4Q of next year towards the tail end of 2026, right, which is plenty of runway to allow us to have the 2 data readouts that I mentioned before. The Parkinson's readout is expected in May, the Long COVID readout is expected in the summer, right? We do not anticipate needing to raise cash between now and those readouts. I can never say that we will never do it. Somebody comes to me with an offer that cannot give up, cannot refuse, I'll consider it, right? But at this point in time, we are not considering nor are we actively trying to seek additional funding. We have sufficient cash to go beyond the 2 catalysts that we expect for next year.

Thank you, Cuong. And coming up on an hour now. So I think we will just try to wrap things up here. Just sort of a final question. What milestones should investors expect over the next 12 months?

We have a good number of milestones coming up and this is part of the reason why I believe BioVie represents a terrific investment opportunity for investors who have a 12- to 18-month planning horizon. We have a Parkinson's trial that is almost fully enrolled. That trial is expected to read out in May, which will provide a catalyst at that point. Our Long COVID trial is expected to be fully enrolled in February, which puts us in the position to have top line data readout in the summer. We also have an ascites program that is frankly the most derisked program I've seen in my career of developing drugs, right? And we are exploring a number of funding opportunities that may be able to allow us to start that trial sometime next year.

Any one of those 3 programs will create significant upside for shareholders and put the numbers on to these. Parkinson's, we believe, could become a $3 billion to $5 billion annual sales opportunity in the U.S. alone for bezisterim.

Long COVID, if you just take 10% of the 3 million Americans who suffer from the most severe form of Long COVID. This could become a multi-tens of billions of dollars drug as well. And the ascites drug could be easily $1.5 billion to $2 billion annual sales drug. In any way you want to discount, risk adjust these drugs. It will lead you to a value that is significantly more than our current market cap of $10 million to $15 million. We unfortunately have been left for dead and essentially been ignored just like many other micro-cap biotech companies. We are trading, our market cap is less than half our cash, right? And that's the reason why we spend a lot of time trying to tell the market about our story, and we try to prepare everybody for the catalysts that are coming in 2026.

So 2 major data readouts in 2026. That would hopefully provide catalyst for our share price in our stock. With that, I thank you very much for your time this afternoon. If you are a current investor, thank you for your support. We hope that next year will be a pleasant one for our shares, right? And the -- for those that are not shareholders, really study what we do and considering -- weigh the facts. And we hope that you fully get to understand our story.

There was a question we did not get around to as to why there has not been more insider buying. The reality is I have participated and bought every time that the lawyers have allowed me to do so, right. I am a strong believer in this drug, not only because I'm the CEO, right? I'm putting my money where my mouth is. At one time, I was one of the largest shareholders in the company as well. But because I have nonpublic material information, I often cannot invest and buy more shares, right? And that is the same with much of the management team.

All right. So with that, I thank you for your time. I wish you a great day. Thank you very much. Bye-bye.

Thank you, Cuong. And for our audience, if you do -- for more information on BioVie, you can always give us a call here at RedChip at 1-800-REDCHIP or you can e-mail us at [email protected], which is the ticker symbol [email protected]. And of course, you can also visit the redchip.com website to the BioVie page at biviinfo.com. There you can actually view and download the investor presentation, fact sheet. You can also sign up for news alerts to stay abreast of all the developments as they happen.

With that, I want to thank all of our attendees for their time today. And again, thank you, Cuong, for once again joining us, and we look forward to having you back.

Thank you. Have a good day.

Hello. This is Craig Brelsford with RedChip Companies. Thank you for joining today's event with BioVie, which trades on the NASDAQ under the ticker BIVI. With us today, we have Cuong Do, President and CEO of BioVie. We will begin with a brief presentation in a moment and then we will answer your questions. Submit your question at any time by using the Q&A tool at the bottom of the Zoom window.

Before we begin, please allow me to read the safe harbor statement. This call may contain forward-looking statements within the meaning of the Private Securities Ligation Reform Act of 1995. All statements pertaining to future financial and/or operating results, along with other statements about the future expectations, beliefs, goals, plans or prospects expressed by management constitute forward-looking statements. Any statements that are not historical facts should also be considered forward-looking statements. Of course, forward-looking statements involve risks and uncertainties.

I now turn this webinar over to Cuong. Go ahead.

Good afternoon, Craig. Thank you for joining. Good afternoon, everyone. Thank you for joining our update today. I'm very excited to share with you this afternoon some exciting progress at the company, right?

As you know, we have several clinical trials underway right now, which makes it -- I believe we have one of the most exciting biotech companies around with an exciting portfolio. You may know that we have a Parkinson's clinical trial that is underway. It is a Phase II trial, and now we can pick up -- enrollment has picked up relatively quickly within the last few weeks, and we can now project to be fully enrolled by the end of 2025. As a result of that, we would expect top line data readout in the May April time frame of 2026. So this is a very exciting progress for us, and I'll describe more about this trial in a moment.

You also may note that we have a long COVID Phase II trial that is underway as well. That trial is enrolling very well, and we expect to have further guidance when that will be fully enrolled in about a month. The enrollment is going very well. We just really want to see how that is coming along in the next few weeks and when we'll get full guidance at that point in time.

We also like to announce that our ascites Phase III clinical trial has been submitted -- protocol has been submitted to the FDA, and we should hear back from the FDA any moment now. We submitted this 3 weeks ago, and we typically hear within 30 days. So that 30 days should be coming up next week. And the exciting thing to announce is that we have significant cash runway. We have sufficient cash to go to the end of 2026, which is, of course, well beyond the timing of when the Parkinson's and the long COVID trial are expected to read out.

So just an overview. As you know, our lead asset is a drug candidate known as bezisterim that modulates the production of TNF-alpha, which is considered to be the master regulator of inflammation. In clinical trials, bezisterim has shown to be able to reduce inflammation and the associated insulin resistance.

In our Parkinson's trial, Phase II trial, Parkinson's patients have seen improved muscle control. Alzheimer's patients have seen improved cognition and function, and all of these patients have seen the lower levels of DNA methylation, which is essentially changing the biological aging process.

Our second drug candidate is BIV201, which hopefully will become the first therapeutic for ascites, which is a terrible condition that has over 50% mortality rate within 12 months.

As you know, we believe that chronic low-grade inflammation is the starting point for many things that go on in the body. And it all starts with TNF-alpha, which is considered to be the master regulator of inflammation. When you have TNF-alpha present, it just drives more inflammation. It creates a forward-feeding pro-inflammatory cycle that just creates -- that produces more TNF-alpha, more cytokines, chemokines, which of course has been associated with a large number of diseases.

When you have inflammation, TNF-alpha, it derives its resistance that's been associated with Parkinson's and diabetes. And of course, TNF-alpha drive something called DNA methyltransferase 3A and B, which accelerates DNA methylation, which has been associated with a large number of diseases. And our drug candidate directly impacts the production of TNF-alpha. It's been -- and it works through something called ERK and NF-kappa B.

Now it's been known for decades that ERK plays two very different roles in every -- practically every cell in our body. The first involves insulin signaling, whereby insulin works through several pathways and essentially affects all -- and ERK helps affect all the cellular growth repair and regeneration activity that goes in all of ourselves. But it's also been known for all this time that ERK plays an important inflammatory role as well, whereby different extracellular signals, such as different cytokines, chemokines would come into the cell, it would activate ERK, which then activates NF-kappa B to lead the production of TNF-alpha. And as I mentioned earlier, TNF-alpha then drives a forward-feeding pro-inflammatory cycle, that leads to more TNF-alpha, right?

And so it's obvious what you want to do, you want to block what's called inflammatory ERK without touching hemostatic ERK. But unfortunately, that's much easier to than done because dozens of teams over decades try to do it, but no one was able to find a selective enough inhibitor of just inflammatory ERK. And that's where, frankly, we got lucky. We did not set out to do this. We just had our eyes open to recognize that our drug candidate, bezisterim, blocks the activation of ERK and NF-kappa B, right?

So we are not blocking ERK itself, right? And that's why we do not suffer from the toxicity problems that have plagued all the prior ERK inhibitors. What we are doing, bezisterim is blocking the activation of ERK into its active form, something called PERK. And without PERK, you're not going to have activated NF-kappa B and as a result, you block the production of TNF-alpha, which is a huge deal because this is the starting point for many things that comes after it in various disease cascades, one of which, of course, is Parkinson's.

It's been known for quite some time now that 2 conditions need to be true at the same time for a patient to develop Parkinson's symptoms. The first is you need low dopamine levels in the brain. And the second is you need inflammation and the associated insulin resistance. If you're somehow able to just reverse the insulin resistance in the brain, the body is able to make use of the dopamine that's there to restore muscle function. And over the years, people have tried lots of crazy things, including using inhaled insulin as shown here, right, to try to get a little bit more insulin into the brain so that you can reverse the insulin resistance and free up that glucose. And it does work, right?

As you can see from this data, if you're able to get enough insulin into the brain, it reverses the muscle loss, right? The body is able to make use of the dopamine that's there. But that, unfortunately, is not a very practical solution. And that's why to this day, the standard of care in Parkinson's remain the drug called levodopa, which was introduced over 5 decades ago. And now levodopa remains the standard of care for a reason. It is a very, very, very good drug in helping to restore muscle control.

But it does have some deficiencies. The first is that it has a short half-life, which means Parkinson's patients have to take it every 3 to 4 hours or 5 hours because it wears off very quickly. That has a short half-life. The second is that it's activities wanes over time so that the longer you stay on the drug, the higher dose you need to get that effect. So over time, as you get higher and higher doses, it causes something called LID, levodopa-induced dyskinesia, which is a trembling effect.

So when you have LID, all you can really do is cut back on the dose of levodopa and wait for the dyskinesia to pass. But as you cut back on the dosage, you lose muscle control and therefore, are not able to move, which is a terrible trade-off that Parkinson's patients have to go through. And what we found in our preclinical studies in rodents and nonhuman primates is that bezisterim is equally effective as levodopa in restoring muscle control.

Now that is a huge statement in and of itself because no drug over the decades have been able to be equal or better to levodopa in restoring muscle control. But what we also found is that we give it in combination with levodopa, you saw a synergistic effect, whereby you saw the greatest muscle control. Now that is a huge deal.

What we also found at the end of the trial, when we sacrifice the monkeys and look at their brains, we found that those that were treated with bezisterim retained twice as many neurons as those that were treated with placebo, right, suggesting that there is a neuroprotective property to the drug, right? And we're grateful to the Michael J. Fox Foundation for having funded this trial to help us understand that there is a potential neuroprotective property to the drug, which for us is actually not at all surprising because we know that bezisterim reverses insulin resistance, which means there's greater glucose availability in the brain. We also know that system enhances blood flow to the brain, which means there's greater oxygen available in the brain. So when you have greater glucose and oxygen availability in the brain that only bodes well for better neuronal health.

So based upon this preclinical data, we went into the clinic and enrolled 40 patients with moderate to severe Parkinson's, and we essentially replicated in these patients, the study that we did in the nonhuman primates, whereby we treated the patients for 28 days. We gave half of them a placebo and levodopa or essentially just levodopa alone, as shown here in red.

We also gave half the patients bezisterim and levodopa as shown in blue, and as you can see, those that were treated with levodopa experienced about a 3-point improvement or a superiority on what's called the Part III score or the motor control score of the unified Parkinson's disease rating scale. Now that is a clinically meaningful difference, right?

And what more is that, that is on top of the tremendous improvement that levodopa produces by itself. So this is a huge deal. But if you look at patients who are younger than 70 years old, who -- presumably whose disease has not progressed quite as far, that difference is closer to 4 to 5 points, which is a huge deal that hasn't been seen very often. But the other thing that we observed has to what's called the time 0 muscle state.

As I mentioned to you earlier, bezi -- I'm sorry, levodopa has a short half-life. So the studies -- the way the study is conducted, and this happens every single day for hundreds of thousands of Parkinson's patients is that they would take their evening medication and go to bed. And overnight, levodopa would wear off. So that first thing in the morning before they take the evening -- the morning medications, none of the patients that were in our trial that were given placebo and levodopa, essentially levodopa alone, had control of their muscle first thing in the morning. So their muscles were in the off state. So they were stuck and rigid and so forth. And they had to wait -- take their morning medication and wait until it kicks in before they had restoration of muscle control.

In contrast, roughly 1/3 of the patients that were given as bezisterim have control of their muscles first thing in the morning. They can move. They can get out of bed. Now that has just never been seen before. And that, of course, is all because bezisterim has a long half-life. It lasts for 12 hours, whereas levodopa last for maybe 3, 4 to 5 hours at most post. So this trial gives us the first proof of concept in humans that shows that we can give levodopa alongside bezisterim and help moderate to severe Parkinson's patients improve their muscle control. And this establishes the first half of what we're trying to do in Parkinson's.

And we are now conducting a second study to demonstrate the second part of what we're trying to do in Parkinson's, which is to show that bezisterim could be used as first-line therapy as monotherapy in Parkinson's. So we are enrolling 60 patients in a clinical trial where we will give half the patients placebo, and then the other half, we will give them bezisterim alone. And the trial will go for 3 months and what we're hoping to show in this trial is that over the course of 3 months, bezisterim can help slow the progression of the disease, slow the progression of muscle loss for patients who are treated, whereas those that are on placebo will continually have a worsening of their muscle control, right?

This trial, as I say, is underway. This trial is expected to be fully enrolled by the end of the year, and this trial is expected to have data readout in April or May 2026, right? So this is a very exciting development for us. This trial was slow to enroll. The enrollment has picked up significantly in the past few weeks, months, and we are now expecting full enrollment at the end of the year.

So now let me move on to long COVID. The world really has moved on from long COVID. Everybody assumed that it's behind us and so forth. But the reality is thousands of Americans are getting infection every single day. And 17 million Americans currently suffer from the debilitating symptoms of brain fog, fatigue and malaise associated with long COVID, and 3 million Americans have these conditions so severely that they have had to quit or change their jobs, simply because they can no longer put up with the physical demands of their job, and there are no treatments out there today, right?

And it is unbelievable to me. I did not know this, but there are huge, huge long COVID centers and major academic centers around the country that are trying -- such as Yale, Mayo Clinic, Stanford, UCSF and so forth, that are trying to treat these patients using any combination that they could simply because there's really no treatment for long COVID as it stands. And within the last couple of years, researchers have been able to tie the symptoms of long COVID through inflammation, right?

It's believed that long COVID, essentially despite proteins that remain in the body after the infection has been thought fought off, works through something called the TLR4, the toll-like receptor 4, and the spike protein, the E protein, the envelop proteins, also works through the toll-like receptor 2, both of which worked to activate NF-kappa B and ERK in the cell. And since bezisterim has been shown to modulate the activation of ERK and NF-kappa B, there is good reason to believe that bezisterim may be able to modulate the inflammation that comes from these -- the spike protein and the envelope protein that continues to circulate around in the body. So that is the reason why that we have been given a $13 million grant. In fact, we are the only company that has been given a grant to test a therapeutic to see if it can address the CNS symptoms of long COVID. The CNS symptoms, of course, being brain fog, malaise, fatigue that goes along with long COVID.

So we are currently enrolling 200 patients in a trial that is fully supported by our grant. We are randomizing the patients half to placebo and half to bezisterim, okay? And this trial essentially runs for 3 months and then that trial, like I said, is currently underway, and we hope to give full guidance on when the trial will be fully enrolled, but we expect this to be on track for a data readout in the middle of next year, right? Again, a second data readout in 2026.

With that, let me also move on to ascites. Ascites is the origin of the company. This is where the company started before we made the acquisition of the bezisterim that brought us into the CNS realm. Ascites is a terrible, terrible end-stage liver disease. By the time you develop ascites, the liver has gotten so scarred that it's not able to process fluid the way it normally does. And it then also starts to affect the kidney. And as a result, fluid starts to build up in the abdomen, right? And there are no therapies approved for ascites. And so literally, the only thing that you can do is stick a large needle into the abdomen and physically remove the fluid that has accumulated there. But since nothing has been done to address why the fluid accumulates in the first place, these patients are back in the hospitals every 1 to 2 weeks to get another 5 to 10 liters of the ascites fluid removed. Now you can just imagine the strain that that's up to the body, right?

And so frankly, the only treatment objective at this point in time is to keep the patient alive for as long as possible so that he or she hopefully may qualify for a liver transplant. And since there are not enough livers to go around, the life expectancy, the mortality rate, I should say, for this condition is over 50% over the course of 12 months. And our solution is a drug called terlipressin. We put our drug into a small saline bag. We hook it up to a portable infusion pump that patients wear on their belt, and we slowly infuse the drug in over the course of the day. We conducted a Phase IIa trial that showed that the drug was safe. There were no severe adverse events that were drug related.

We then continued on to a Phase IIb trial to try to demonstrate efficacy of the drug. The plan was to enroll 30 patients in a trial, right? But halfway through the study, after 15 patients were enrolled, we had already received statistically significant data that show that those that treated with our drug, BIV201, saw a 50% reduction in the ascites volume, whereas those that are under standard of care saw no change. And as I mentioned, this is a condition that has 50-plus percent mortality rate within 12 months. So that's why we concluded, the only ethical thing to do was to stop the trial early and to engage the FDA in a conversation in what -- on what it would take for us to proceed to Phase III trials for registration.

And since we've already received fast track and orphan designation from the FDA, we only need one trial to register the drug. So as of now, we have had conversations with the FDA. We have received all the feedback we need from the FDA to design the trial, which we have done, and we have submitted the Phase III protocol for the trial to the FDA that was done 3 weeks ago, and the FDA has 30 days to respond to our protocol, and that 30 days is expected to be up next week.

So by the end of next week, we expect to have comments back from the FDA on any changes, if any, and we don't expect any, which would then allow us to proceed to Phase III. This trial is currently underway pending different fundraising mechanisms. We are in various discussions to see how we can raise $25 million to fully fund all of the work that would need to be done between now and registration for this drug, right? And this, for us, is a big deal that would save a lot of lives.

To kind of give you a sense of the magnitude that we're talking about here, there are about 1 million Parkinson's patients in the U.S. today. And if with just 10% penetration of that market, we believe that our bezisterim for Parkinson's could be at least the $3 billion to $5 billion drug annually in annual sales in the United States. And with ascites, we believe this could become a $1.6 billion to $2 billion drug in annual sales in the U.S. alone, right? So any way that you want to risk adjust or discount these numbers, it would still lead you to a number that is substantially larger than our current market cap of $15 million, right?

So that's why I continually tell people that I believe we represent a great investment opportunity. We are the rare biotech companies that has significant cash runway well beyond catalyst. We will have 2 data readouts in middle of next year in second quarter and maybe over the summer of next year. Our Parkinson's trial is expected to read out in April or May. And our ascites trial is certainly going to be reading out in the middle of next year, right? So we represent that company that has cash. We have a company that has multiple data readouts, right? So I believe we represent a terrific investment opportunity for investors who have a 12- to 18-month planning horizon, investment horizon because we believe there is good reason to believe that these trials will be positive, right?

With that, let me stop it here to see if we have any questions in the audience.

Thank you very much, Cuong. [Operator Instructions] As some persons already have done, Cuong. What is the size of the market for your ascites drug? What do you expect the FDA to do by the end of the month?

Right. For ascites, there is no drug available on the market right now. So we have taken a very conservative estimate to size the market, right? And that leads us to believe that our ascites drug, BIV201, could have annual sales of somewhere between $1.6 billion and $2 billion in the United States alone, right?

And there was a question about what do we expect from the FDA by the end of the month right? Frankly, we expect them to not have any comments, which essentially means that we are then authorized to move on to Phase III when we have the funding to do so.

Okay. Well, we have someone who wants to speak to you, Cuong. Lance, please unmute your line and Cuong is ready to speak to you.

Yes. I was wondering with the ascites, do you have any information or any follow-up on the patients that were in the Phase II trial, the ones that did so well? Do you have -- is there any follow-up on that information?

We have some anecdotal follow-up. We did not follow up as there was no post-study surveillance, if you will, that was put in place. But we do have anecdotal information that those patients continue to do well. In fact, we have one patient who actually never had to go back to have another centesis because the drug essentially helped address her ascites fluid buildup, which is exactly what we want to see, right? So that was some -- that is very encouraging. And part of the -- that gave us some of the information that we needed to go and design the Phase III trial the way that we did. So hopefully, that answers your question.

It did. I have another one, quick one. with the ascites, you've been looking for a partner ever since that trial, which I don't remember was it a year, 1.5 years ago or along the lines, and you haven't found anything. What makes you think that you'll be able to find somebody now?

That's a very good question. As we look at out there, the most logical partner for us is a company that was going through its own difficulty, right? They were bankrupt. They've been acquired by someone else. And for that company, this represents a small opportunity. That's why I think that just doesn't quite work out for them. There are 2 other companies that we were in discussions with, and they're highly interested in this. But frankly, they, like us, have had difficulty raising capital as well. And as you know, the Baltic capital market has been brutal, absolutely brutal over the course of the last 2 years. So those companies, like us, have been keeping their eyes open for opportunities to fundraise. And we believe that the capital markets are beginning to open up a little bit that gives us some hope that over the course of the coming months, capital will become available for us to either individually -- jointly fund the trial or to essentially fund the trial through a different kind of partnership that we're exploring.

Thank you very much, Lance. Cuong, what is the status of the once daily bezisterim pill?

Yes. That is the -- let me -- to explain that, bezisterim is currently administered twice a day. Patients would take one capsule in the morning, one capsule at night, right? And the -- obviously, when you're trying to address a population like Parkinson's or Alzheimer's, once a day would be much, much better. So we have initiated and frankly, we have slow walked the development effort for a once-a-day drug, simply because we know we can -- we know it can be done, we know what needs to be done, but it will cost us about $1 million to $2 million to fully develop that once-a-day version, right? And so right now, what we want to do is to focus our resources on the Parkinson's trial and the long COVID trial just to make sure both of those readout. And once that is behind us, we'll then pick up on a once-a-day version. And that is probably the version that we will take into the Phase III trial for Alzheimer's and for Parkinson's as well. Thank you for the question.

Cuong, you may be having bandwidth issues and I'm suggesting that you cut your video and go only -- yes. Thank you. Thank you. [Operator Instructions] Cuong, we already have some questions here written in. Why do you only feel 10% of Parkinson's patients would take bezisterim? I would think, given the results so far, every patient would want it.

I share that optimism, right? But I think the safe thing to do is to forecast a modest penetration and then let it grow over time. I would much, much rather under deliver -- under promise and over deliver rather than overpromise and underdeliver. It goes back also to the fact that bezisterim is a -- I'm sorry, levodopa is a very, very good drug. And if you're already on levodopa, you then would need to take bezisterim top of it, right, which at the time that we launched the drug, we would not have the indication for it. We expect to launch bezisterim as a monotherapy to go after newly diagnosed patients, right? So that is a population that needs it the most.

The reason I say that is that the moment you are diagnosed with Parkinson's, you know you are on a one-way road of neurodegeneration and your muscle control will only go down. So the faster that you can get on to a drug that can help slow that decline, the better for the progression of your disease. And so frankly, from a good of humanity standpoint, that's exactly what we want to do is to help those patients slow the progression. So that is our first indication.

Our second indication is we will go back and redo our Phase II, which gives bezisterim in addition to levodopa to essentially get the market as a combination, right? But early on, we want to be safe, conservative, small forecast. Of course, there's going to be some off-label use where clinicians will give bezisterim to patients who are already taking levodopa, we're not going to forecast for that. We're going to wait until we actually conduct the Phase IV trial that gives bezisterim with levodopa, show that it works, get the claims for it, then we will go and market for it. But that, of course, will take us into well beyond the 10% that we're conservatively forecasting now. Like I said, we would rather under promise and over deliver rather than the other way around. I hope that answers your question.

Thanks, Cuong. Have you had any discussions with any major pharmaceutical companies for funding?

Thank you for that question. Over the last couple of years, we have had a number of conversations with large pharmaceutical companies that are interested in Alzheimer's, Parkinson's and CNS diseases. A number of them have actually shown interest, great interest in this mechanism of action because this is a very novel mechanism of action because as you know, in Alzheimer's, everybody has been talking about amyloid and to some extent tau for decades, and there's never been a drug that can essentially address amyloid and tau, which then also significantly alter the disease and slow cognitive decline, right? And we represent the first new mechanism at work in Alzheimer's and Parkinson's in decades.

But in pharma, and I understand where they're coming from, because I've been on that side of the table as well, the road is littered with promising drugs for Alzheimer's and Parkinson's that fail in Phase III, right? And in big pharma, no one is ever fired for playing it safe, right? And so the reception that we have gotten from big pharma has been they wish us well, right? They really are wishing us well. They're monitoring us, and they basically tell us come back when you have positive Phase II or Phase III data on this trial and then we'll pick up the conversations there, right? So there's interest in our molecule, they're monitoring it, and they're just really waiting for Phase III data in Alzheimer's and possibly Phase II, more ideally Phase III data from Parkinson's trial. And so I do not expect us to ever commercializing these molecules. My expectation is that when we demonstrate positive data, we will out-license the molecule to big pharma or frankly, they will acquire our company, right? That's really the realistic outcome to expect in for our company. I hope that answers your question.

How long would a Phase III trial last for ascites?

This trial is unfortunately a trial that's going to take some time to enroll. We need to follow the patients for 6 months, right? So in theory, this trial is short, but the enrollment rate here will be relatively slow, right? And so we would expect to start the trial, to conduct the trial in both Europe and the U.S. with some significant centers that work with these patients, right? But even that, this trial will take us at least 18 months, possibly 24 months from beginning to end, right? And that's part of the reason why we did not prioritize this earlier is that it will take some time and $25 million to fully complete the study and to register the drug. Hopefully, that answers your question.

What is the status of the class action? And is it a large drain on resources?

To be honest, it is not a large drain on resources, right? Where it stands right now is we are in discovery stage. We had essentially -- the way it works is that we put in our petition or motion to dismiss the trial at the very first stage. And frankly, the way -- and that was not granted. And the way it was not granted is, frankly, the judge bought our answers to virtually every argument, but the judge had a couple of other questions that were still unanswered in his mind -- in her mind. And the -- and as a result, she asked us to go into discovery and essentially answer those questions. So we are now in the discovery mode, whereby both the plaintiffs and us are essentially look -- answering questions, putting up answers to various questions that were being asked. And once the discovery stage is over, we will then essentially put in place another set of questions for summary judgment.

And as you should know that, unfortunately, many of these class action lawsuits is an insurance game, right? When any time that -- there's significant movement in share prices, there is an entire group of ambulance-chasing lawyers out there that essentially goes out and try to find 1 or 2 plaintiffs or shareholders who've lost some money to essentially try to get a class action suit started, right? Their objective is never to actually sue us or essentially win. Their entire objective is to get an insurance settlement, right, and get essentially payout by the insurance company. And as a result of that, over 2/3 of these suits are dismissed at the motion to dismiss stage or dismissed summarily without ever going to trial, right? And then a small minority of these -- and then the remainder essentially are negotiated settlements, right?

And the way it works is that we're now in the discovery phase, as I mentioned, we will eventually file our motion to dismiss. We believe that will be granted. And you should also note that our attorneys that are working on this has an 80% dismissal rate of these suits compared to the industry average of about 2/3. And even if the suit is not dismissed, we believe we'll settle it and we are still well within our insurance policy for the settlement of this suit. So frankly, it's not taking that much time. It's really the lawyers going to the motions of it right now. Hopefully, that answers your question.

Could you clarify ascites please, Phase III trial begins mid-2026, and lasts 18 to 24 months?

That is our hope is that if we get the funding for the trial such that we are able to initiate it mid -- whenever we initiate it, the trial, let's say, will be expected to run for about 2 years. That is how the Phase III trial will work for ascites.

We have time for a few more questions. [Operator Instructions] Cuong, INmune Bio was another company focusing on TNF-a and its recent clinical results were not as good as hoped. Did that trial provide any useful information about the method of action of bezisterim?

Thank you for asking that question. And INmune Bio, of course, is one of a small handful of companies that work on inflammation as the mechanism to address disease. And that trial rebolstered our conviction that bezisterim is the correct approach, okay? The INmune Bio's approach is not to block the production of TNF-alpha as bezisterim does, but to actually hope to try to mop up and block the activity of TNF-alpha after it has already been produced, right, which is downstream. And once you have all the TNF-alpha in the body, mopping it all up is very, very difficult, right?

And you know that is -- excuse me, the case from the entire class of antibodies now known as anti-TNF, right, such as Humira, Stelara and so forth. These anti-TNF antibodies have been around for decades. That's why Humira still remains a multibillion-dollar drug that it is right now. And the experience with these antibodies, these anti-TNF drugs, shows that it's actually very difficult to mop up and block the activity of TNF-alpha once it's already there. And unfortunately, INmune Bio is doing exactly what those antibodies are trying to do in a different and a small molecule. It just doesn't work quite as well, although we know there is a signal, and we know that blocking TNF-alpha can work.

And what I -- the reason I say that is there have been large population of studies out of the NHS and here in the U.S., Mayo Clinic and other places, that looked at patients who are taking anti-TNF medication. And what they found is that for those that are taking anti-TNF medications, those patients have a 50% lower risk of developing Alzheimer's compared to those who are not taking anti-TNF medications, right? And of course, the Humira and so forth, do not cross into the blood brain barrier, right?

So it doesn't really help directly with getting into the brain. But the mere fact that you're reducing the TNF-alpha burden systemically for these patients also help reduce some of the CNS burden of TNF-alpha, right? So it just shows that if you're able to reduce TNF-alpha, you reduce the potential risk of developing Alzheimer's. And that is part of the reason why we have even greater conviction now that bezisterim is the right way to go. And by blocking the production of TNF-alpha, we believe we block all the downstream negative consequences that comes along with that, which then should help us not only with Alzheimer's, but with Parkinson's, the long COVID as well.

Thank you very much, Cuong, and thank you, everyone, for all of your questions. For more information about BioVie, reach us at 1-800-REDCHIP or e-mail us at [email protected]. Please visit RedChip's Investor Information page for BioVie. It's biviinfo.com. There, you can view and download the investor presentation and fact sheet and sign up for news alerts on BioVie.

Please be sure to watch Small Stocks, Big Money, RedChip's program featuring exciting small cap companies every Saturday night at 7:00 p.m. Eastern on Bloomberg USA.

Join RedChip's next webinar with FatPipe on Wednesday, October 15 at 4:15 p.m. U.S. Eastern. Register for all RedChip webinars at redchip.com/events, where you can also view an archived version of today's webinar. Thank you to our many participants today, and thank you, Cuong.

Thank you. Have a great day.