BioVie Inc. (BIVI) Earnings Call Transcript

Hello. This is Craig Brelsford with RedChip 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; Joe Palumbo, Chief Medical Officer of BioVie and Mark Stacy, a key opinion leader and the William E. Murray, Professor of Neurology, Movement Disorders Division at the Medical University of South Carolina. 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 fact should also be considered forward-looking statements. Of course, forward-looking statements involve risks and uncertainties. Team BioVie, please go ahead.

Thank you, Craig, and thank you, everyone, for joining today. Before I start, I would like to thank everyone who's worked so hard for so many years to get us to where we are today. Our team has worked countless hours, sometimes pulling all-nighters and so forth, weekends, to get us here, right? And it's on their behalf that I'm speaking to you today regarding this. I would also like to acknowledge two people in particular, it's Clarence Ahlem and Chris Reading, who are senior members of our team who literally have spent decades of their life working on this to get us to where we are today, that they are -- we call them affectionately -- the -- we affectionately call them the fathers of bezisterim. So Craig has -- I will let you read at -- by your leisure. But let's start with Bezisterim. What is bezisterim? Bezisterim is a small molecule that is orally bioavailable. So patients take it twice a day, a capsule in the morning, a capsule at night. It freely crosses the blood-brain barrier, and it's believed to block the activation of something they called ERK and NF-kappa B. When you block NF-kappa B and ERK, you block the production of TNF alpha. And therefore, what you're doing is you're breaking the continuous forward-feeding proinflammatory cycle that essentially is going on. So by blocking NF-kappa B and TNF alpha production, it is also believed that it's blocking the activation of something called IKK and JNK, which is essentially implicated in insulin resistance. IKK and JNK, when it is activated binds to something called the insulin receptor substrate 1 and 2. And when it binds to IRS 1 and 2, it prevents insulin from binding there. So that's the direct linkage between inflammation and insulin resistance. And that's the key to how bezisterim works. We conducted the SUNRISE-PD Phase II trial to figure out what to do to get the data that's needed to design the Phase III trial. So the SUNRISE-PD was designed as a short 3-month long study. It is a classical signal finding study to essentially identify which endpoint can we get an efficacy signal, right? So which endpoints have the most favorable treatment benefits. Is the measure, the magnitude of this difference to identify the populations where the drug works best for and all of that allows us to design and size the Phase III trial. And that is the critical trial, right? So that's the trial where you basically say, what's the primary endpoint? And did you meet your statistical significance or not? That's the thing that really matters, right? It's in the Phase III trial. The Phase II trial is signal finding. It's trying to get us the information so that we can do that in the Phase III. So in this Phase II trial, we evaluated a series of motor and non-motor endpoints. We created something called the Early Parkinson's Neuro-inflammation Composite 15, which is the EPNIC-15 and we will go in much greater detail -- much more detail about that as -- over the course of this presentation. We looked at the classical metrics of Parkinson's, something called the Motor Disease Society's Unified Parkinson's Disease Rating Scale. It has 3 parts. Part I deals with non-motor symptoms. Part II deals with activities of daily living, Part III is motor and then you add them up to get the total score. We also looked at something called the Parkinson's Disease Sleep Survey, number two, at sleep. We looked specifically at sleep because in our prior trial, we saw a signal on sleep. We also looked at quality of life, using something called PDQ-39. In addition, we evaluated a series of biomarkers, and we conducted a -- what's called a proteomic study that evaluated 380 different proteins in our blood plasma. And as part of that battery, we looked at biomarkers of neurodegeneration, we'll come back much more to this, but I especially love NfL, which is neurofilament light and GFAP. We looked at neuroinflammation, and we also looked at peripheral inflammation. So that's what we try to do. That's what this study was designed to do. And this is what we found. We found that patients treated with bezisterim appear to have experienced a statistically significant treatment advantage compared to those on placebo. We looked at the clinical outcomes. Where we saw significant impact on EPNIC-15. We saw that 283 out of the 380 proteins we looked at moved towards a direction that's beneficial. That's been shown by others to slow the progression of disease. We looked at different metrics of neurodegeneration, and those moved in a very beneficial manner. And of course, we looked at various measures of inflammation. We also saw that while bezisterim appeared to have an effect across the trial population, we also found that our hypothesis that patients who have higher inflammation at the start of the study would be the ones that benefit the most and would respond the fastest, and that's exactly what we found. Those with higher inflammation at baseline that experienced statistically significant advantages over placebo across all clinical measures that we looked at including UPDRS Parts I, II and III and the total score as well as EPNIC-15. I'll share more of that as we go along. The biomarker results also suggest that bezisterim may be slowing neurodegeneration over time. This is a big deal if we can show this. And certainly, this is something a hypothesis that we would be testing as we move into Phase III registrational trial. And lastly but not least, bezisterim continues to demonstrate a very safe profile. It was well tolerated. The safety profile was very similar to placebo. Before I go into deeper, let me set the context for why these data are so important. First of all, we know that Parkinson's is an aggressive neurodegenerative disease. Once you have it, the brain cells will continue to die. Neurodegeneration will continue to happen. Right now, the community largely view Parkinson's as a motor disease, characterized by low dopamine levels in the brain, which then leads to muscle disorders and slowing motor symptoms. But unfortunately, it misses all the non-motor symptoms right now. And since that is such an important part of this, I'm going to dive deeper into non-motor and we will spend a lot of time on non-motor discussions. We found this chart in a great journal article. So frankly, we just liberally borrowed it. We copied and pasted it here. The green at the bottom discusses non-motor symptoms. Non-motor symptoms include sleep disorders, depression, cognitive slowing, GI symptoms and a lot of constipation. And the important thing to note here is that many of these non-motor symptoms exist for years, many, many years before the actual diagnosis of the motor symptoms. And these non-motor symptoms continue to worsen, and some patients would say that's the non-motor symptoms that could be worse than the actual motor symptoms themselves. And when it's diagnosed somewhere along the way, patients will get put on to therapy and the current standard of care for Parkinson's treatment is levodopa, which is a great drug that's been around for over 5 decades. But treatment with levodopa and similar drugs also create their own treatment complications as well. And the thing to note about this chart is that it all heads upwards. The disease continued to progress. Things always get worse. It never changes and never gets better. And that's where we believe is the big unmet need. And what we're trying to do with bezisterim and the unmet need that we're trying to address is conceptually depicted on this chart. So the dash line at the top, think of it as the top line on this chart. The disease, if untreated, will continue to progress. But then as you get put on to levodopa, what you're doing is that you are shifting that curve down because you are addressing the motor symptoms of the disease, right? So you're shifting this curve down. But since nothing has been done to address the underlying reason for the disease progression, disease continues to progress. What we're trying to do is -- and we believe the big unmet need in the community is something that changes that trajectory, something that can slow the progression and essentially bend that curve, right? As I move on, let me ask that my -- others that are in the panel, Mark and [Terren], I'm not sure why you're on the panel, if you can just take yourself off camera, right, and mute yourself as well. Thank you, and Joe as well. Okay. So we know that bezisterim works on inflammation. So the inflammation, the neuroinflammation hypothesis essentially shows that -- it goes something like this. It's peripheral inflammation that's activated by TNF alpha and NF-kappa B as I showed before, essentially leads to neuroinflammation and oxidative stress, ER stress and so forth in the CNS, which then leads to neuronal loss, which then leads to clinical progression. That's the hypothesis for what's really going on, right? And this hypothesis is partly driven by -- associated with term called Type 3 diabetes that was coined by [Dr. Suzanne de la Monte] from [Brown], who is also one of our scientific advisers, right? She believes that and we totally believe and many other people believe in her thesis that neurodegeneration has an underpinning metabolic reason that essentially starts with insulin resistance and insulin resistance is caused by inflammation. So what we did in this trial is, again, it's a signal-finding study that is very short and very small, all aimed at getting us the data to design the Phase III trial. So in this trial, we looked at 4 different things. The first is inflammation. So this is really our primary endpoint is inflammation. Does bezisterim has an impact on inflammation? We also looked at what's happening in the -- with biomarkers associated with the disease. The third thing is we spent a lot of time looking at neuronal injury, things such as neurofilament light and GFAP. NfL and GFAP are known biomarkers of neurodegeneration. So they naturally increase in our blood samples as neurodegeneration progresses. And we're asking the question, can bezisterim have an impact on the progression of and the release of NfL and GFAP. And of course, we look a lot at clinical scales. Before we dive into the numbers, let's spend a minute to understand what the numbers mean. We look at the numbers and we look at it for two things. One is just how big of a treatment effect is there. So how big of a difference is there between the treatment group and the placebo group. And statistics has a tool to allow us to do that, to understand that. And that's called the Cohen's d that measures the size of the difference, the size of the effect. Cohen's d of 0.5 is a really good, it's a moderate size impact difference, a 0.8 is a large impact, anything beyond 0.8 is just absolutely massive and huge. And the way to all the numbers are arranged is that a negative value means that's a treatment benefit, right? And as you will see, most of bezisterim's treatment effects are in the large range. So the first thing, treatment effect, how large is it? The second is what's the likelihood that, that could be a fluke or coincidental. So that's why we looked at the p-value. The smaller the P the better, right? And statistical significance is defined as having a p-value equal or less than 0.05. So that's when we say something is statistically significant. It means that it had an impact, and it has a p-value equal or less than 0.05. So let me start by just showing the baseline characteristics. We had 57 patients enrolled in this trial. Roughly half were in each of the arms. The bezisterim arm had 28 patients, the placebo arm had 29. And I'll let you read through this at your leisure. This is available at our website. But as you can see here, the treatment and the placebo arms appears to be balanced at baseline. They were very similar. And while our primary endpoint was inflammatory biomarkers, everybody wants to talk about the clinical outcomes because this is Parkinson's. So let's start there. So in the entire treatment population of 57 patients. We looked at EPNIC-15 and the MDS-UPDRS scores. And across the population, what you see is that patients treated with bezisterim are shown in blue, has a smaller change from baseline, right? Here a positive number means people are getting worse. So what this shows is that patients treating -- treated with bezisterim are getting worse at a slower pace than patients that are treated with placebo, okay? And in the entire population, if you look at the p-values we did not get statistical significance on these different p-values. But this is not uncommon. This happens in the majority of Phase II trials. And remember, the second -- as I mentioned before, the purpose of the Phase II trial is to find the end points where the drug could work and with which populations that it could work. Now we -- I mentioned before, we have a long-held -- have long had the hypothesis that patients with higher inflammation levels at baseline will be the ones that will respond the fastest and the ones that will respond with the greatest impact and that's exactly what we found. The hypothesis was true, turned out to be true. What we found is that patients with higher baseline inflammation as measured by platelet levels that are greater than 230 at baseline, 230 frankly, is we chose that because it's the median. The median platelet counts for the population was 233. So 230 was a convenient number. Half of the population study -- in the study had higher platelets. And what you will see in this chart is actually quite startling. You see that patients to have higher inflammation not only had a slowing -- did not have a slowing or worsening. They improved, right? Patients treated with bezisterim improved over the course of 3 months of treatment. On the Part I score that's looking at non-motor symptoms, Part II score that's looking at activities of daily living and Part III score, which is the motor score. And historically, this is the metric that the FDA uses to approve a Parkinson's drug. And of course, when you add it all together, they improved on the total score as well. And if you look here, the statistical numbers are very high, very high, right? And of course, when you look at the EPNIC-15 and we will come back to EPNIC-15 later. The p-value here is highly, highly, highly statistically significant, right? And before you may start thinking or concluding, well, maybe bezisterim doesn't work for patients who have low platelets or low inflammation, that is not the case at all, right? And you can see that on the next page. This page shows the entire population of 57 patients, arranged by their platelet count at baseline. And what you see on EPNIC-15, on Part I score, Part II score, that slope is very flat. And the vast majority of the patients have the numbers below 0. This is -- we took the bezisterim results, subtracted out the placebo results. And if it's below 0, it means it favors bezisterim. So what you can see is about 80% of the patients regardless of their inflammation level benefit from bezisterim treatment. On Part II, that's for Part II -- so Part II, it's even higher than that. It's only when you get to Part III that you see a slight slope. And here, you see that more -- about half of the patients benefit from bezisterim treatment. So what does all of this mean? It means that we now have what we call an enrichment strategy for designing the Phase III trial because we want to go into the Phase III and be assured that we can win statistically on Part III score because that's most likely what the FDA will want us to demonstrate at a minimum, right. So at a minimum, what that means is that when we go into designing the Phase III trial, we will enroll just more patients with higher inflammation with -- and perhaps, we will stay with platelets, but perhaps we will go with another metric of inflammation, but we know that higher inflammation patients are the ones that respond the most and the fastest. So we will enrich the population, a sample for the Phase III trial. That means we will over-enroll patients with higher inflammation so that at the worst case at a minimum, we will win statistically on Part III. And of course, we will have the conversation with the FDA about including Parts I, Parts II and perhaps even EPNIC-15 as part of our end points, right. Because given this data that you see on this page, we are highly, highly, highly confident that we have a drug that we can go and discuss with the FDA with a trial design that would allow us to get approval at a minimum on motor symptoms by improving motor symptoms. But the data here would suggest that we would be able to have a win on non-motor symptoms as well. So what that means when you step back from all of the numbers is that we believe that bezisterim can become the first drug that could have an impact on both motor and non-motor symptoms of the disease, and that will be a drug that will uniquely meet the currently unmet need from -- in the community, right. So takeaway number one, potentially the first drug to address both motor and non-motor symptoms of the disease. But we did not stop there. We have said that all prior drugs have been approved largely on motor symptoms, right? The Movement Disorder Society, the name itself says it all. So when you look at the last 10 drugs that were approved, 6 of them were based primarily on daily off time, which looks at how -- what portion of a day, how long the time during the day is your muscle in the off mode, so you can't move, they are stiff. Two of the last 10 approvals were based on Part II score, right? So all motor endpoints. We know that bezisterim affects muscle function. We know that from our prior clinical trial, our first clinical trial in Parkinson's. We also know it from this trial, right? But if you use only motor endpoints, right, you're not getting at what we know to be a much broader clinical impact that bezisterim could have, and you would be undervalued what could be the first therapy for both motor and non-motor. And this is where we learned along the way. We started this trial in April of 2025. And it was earlier this year that we learned about something that Biohaven did. Biohaven is a great company. It has a great terrific management team that I personally have a great amount of respect for. And they are known to be working in Parkinson's right now. They started this fairly recently, and they are also known to be looking at the mechanism of having to do something with inflammation. So Biohaven worked with Broadstreet and Pentara. Pentara is perhaps the leading biostatistician in the industry. We have been working with Pentara for many, many years. So they work together to create and publish on something that they called the Parkinson's Composite Scale or PARCOMS, right. Which is their effort, I believe, to see if with one metric, they can get a measure of both the impact on motor and non-motor. So frankly, we just borrowed a page in their playbook. We frankly just copied what they did. We worked with Pentara to create the EPNIC-15 to include these 15 different domains of Parkinson's. These were prespecified. We hypothesized that these are the ones that bezisterim can most impact based upon our understanding of how the drug works. Therefore, that's where the EPNIC-15 comes from. We did it because we wanted a measure, a single measure that can assess both motor and non-motor impact of the drug. And what we found was startling. Let me first focus your attention to the left-hand side of this chart. This chart plots what happens to each individual patient. So each patient is a bar. It plots the change from baseline to see the patient improve as shown by a negative number. That they stay stable, stay the same, shown by a 0, or that they worsen as shown by a positive number. Now let me focus your attention to the left half of this chart. What you immediately see is the majority of the patients that improved or remained stable are the ones that are on drug treatment. They're on blue lines. And remember, this is a neurodegenerative disease. So if we can help the patients slow the progression, prevent them from worsening, prevent them to be -- allow them to be stable with a 0 score that is a win in our book. Conversely, if you look at the right-hand side of this chart, you see that most patients that worsened are the ones that have -- that were on placebo. So as a result, patients that are on bezisterim collectively as a group led to an EPNIC score of a negative 0.04. The placebo group had a positive 0.18 and look at the Cohen's d, look at the treatment effect. It is huge, right? And as a result, the statistics here is highly, highly, highly statistically significant, right? Showing that patients treated with bezisterim had an advantage. Another way of looking at this data is to look at the right-hand side. Here, you see that 25% of the patients treated with bezisterim meaningfully improved over the course of 3 months compared to only 6% of patients on placebo having meaningfully improved. Conversely, if you look at the other end, you see that only 14% of the bezisterim treatment group worsened meaningfully over the course of 3 months, whereas 46% of those on placebo meaningfully worsened. When we look at this data, we interpret it to mean that patients treated with bezisterim experienced a statistically significant and clinically relevant improvement or advantage over the dose on placebo on both motor and non-motor outcomes, right? So let me now move on to the biomarkers. We conducted a study that looked at 380 different proteins found in our blood plasma. Out of that battery, there were 7 that were specific to Parkinson's disease. And we found that all 7 of them move in a beneficial manner, right, that helped that contributed to the slowing of the disease. So statistically significant. We looked at 36 different biomarkers having to do with neuronal injury and over 90% of those biomarkers moved in a beneficial manner, highly statistically significant. There were over 150 different biomarkers of inflammation. And over 75% moved in a beneficial manner but also highly statistically significant. And we named some of those on the right-hand side here. But let me call your attention to the last 2 rows. Here, we did not get 0.05 statistical significance, but we did get what in statistics is known as trending, which is also very good, right? We saw advantages on a beta amyloid -- beta 42 and pTau-127 (sic) [pTau-217], which are known biomarkers of Alzheimer's. Some of you may know that we have conducted an earlier Alzheimer's study that was longer in duration was 6 months long and saw a signal that bezisterim was having an impact on beta and pTau there as well. And we are very excited to pick up that same signal here in just -- after just 3 months of treatment. We, of course, want to dive deeper into neurodegeneration, right? What we found is that in the group treated with -- the bezisterim-treated group, we look at particularly NfL, I especially like NfL, because this is a known biomarker that the FDA has used as the primary endpoint to approve 2 drugs already. One for ALS and one for MS and other is GFAP. And what we found in this trial is that initially that these biomarkers do go up, right? And frankly, we don't know how to explain that yet. No one really knows how to explain that yet. But this is consistent with what has been reported by other studies that test these kinds of drugs. They go up. And in other studies, they slow, they increase, they may be stable. But what we see in our trial, especially with NfL is we see a very rapid statistically significant decline, right. Suggesting that we are slowing the release of NfL, namely we are slowing neurodegeneration. So we also see the same trend for a-beta and pTau, where we are slowing the increase. And so when you put it all together, you see the composite line in blue. We replot that composite line for the bezisterim treatment on the right-hand side and we add to it a composite for all the placebo patients, and you see a very stark difference. The bezisterim treated patients saw a decline from baseline on these neurodegenerative biomarkers, whilst the placebo patients saw an increase. The effect size is good, a statistically significant finding. We also found the information that basically show us mechanistically how that -- how the drug could be working. But in the interest of time, let me move on, skip this. I would just close with the safety information. What we found was the drug continues to be very safe. There were no serious adverse events in the trial, no severe events and certainly 0 deaths. There were only 2 treatment-related AEs, one in the treatment arm and one in the placebo arm, right? And in the treatment arm, that AE was very mild and the patient continued on to the study. So let's put it all together and see what does this really mean. First of all, the drug has an excellent safety profile. In this trial, it is consistent with everything we found to date. Bezisterim demonstrated clear target engagement, has an impact on inflammation, has an impact in the proteomic study, the 380 panel and it has an impact on neurodegenerative biomarkers. There is apparent clinical impact on both motor and non-motor symptoms, has a favorable biomarker for disease modification, right? And it gives us clear rationale for the design for the Phase III. The way that we're thinking it right now is that we would have 2 phases to the Phase III. The first phase would be a 6-month long study that gets at symptomatic relief. We would use most likely Part III score as the primary endpoint and if we use the enrichment strategy that I talked about before, that's how we ensure ourselves a win, a win on statistical significance. But we will also put in there the non-motor symptoms as well. So 6 months the primary endpoint of symptomatic relief. And with the data at that 6-month point, we can go to the FDA and seek approval for registration. But at the same time, with that same patient, we would extend for another 12 months to see if we can get an impact on disease progression. So can we show that we're modifying the progression of the disease. Lastly, we are not all about Parkinson's. We are very excited at Parkinson's. Of course, the results here are phenomenal is beyond what typically would be expected to get from a Phase II trial. But we also have another trial underway that's finishing, if that's our long COVID trial. And if everything goes according to plan, we should be able to report out the data of that in the next 30 to 60 days. We now need to start planning for an end of Phase II trial with the FDA and whereby we would discuss with them the Phase III trial design. So we need to plan, work with our experts to plan the Phase III, start planning for the trials and so forth. And we are -- right now, we have looked maybe a the tip of the iceberg and how much data do we have. We need to continue analyzing the data, prepare for presentations and conferences and continue to submit these to various scientific journal, right? And we will provide additional feedback and readouts over the course of the coming weeks and months as we learn more. And of course, everybody wants to know what's happening with partnering conversations. We will reactivate those in due course now that we have data, right, which is what these -- the larger pharma companies have been waiting for. So in summary, let me just recap that today, we have discussed the top line results for Parkinson's. And we believe bezisterim could become the first treatment in Parkinson's that could address both the motor and non-motor symptoms of the disease. We believe bezisterim can become the first treatment to slow the progression of the disease and may become the first -- a new approach to treating Parkinson's since levodopa was introduced over 5 decades ago. And if we're able to demonstrate that into Phase III, we believe this will be easily a $3 billion to $5 billion annual sales product in the U.S. alone. We did not talk long COVID. The long COVID is coming to an end. We believe bezisterim may become the first treatment for long COVID and given that it affects so many more people that could become a $10 billion annual sales product in the U.S. alone. So with that, I would like to stop my screen share. I would like to ask Dr. Mark Stacy to come on screen as well as Joe Palumbo, to come on screen. And Mark, let me turn it over to you based upon what you've heard me describe here, what is your takeaway? What's -- what are your thoughts about what you've heard?

Well, thanks, Cuong. It's always exciting to think about these data and the more chance I get to look at them the more excited I get. From a more historical perspective, I remember starting my fellowship with Dr. Joe Jankovic, a very famous movement disorders person. And he had just published a paper looking at tremor-dominant versus postural instability and gait disturbance Parkinson's disease. And the scientific world had erupted with disagreement. There cannot be 2 kinds of Parkinson's disease. Now we fast forward for another 40 years, and we're talking about Parkinson's disease as synucleinopathies as alpha-synuclein degenerative disease. And there are statements that occur that we will find hundreds of different causes of Parkinson's disease. And this study underscores that. You've looked at more than 400 biological markers. And in theory, all of them could play a role in a particular type of Parkinson's disease. What you've really found is this platelet marker as a way to identify and enrich this population. And those data are striking. They're striking from a potential neuroprotective standpoint and from a potential motor control standpoint. So I am all in on this. I think this is a very interesting molecule that's going to generate hundreds of new thoughts about how we treat Parkinson's disease, and you're ahead of the curve.

Well, thank you, Mark, for those comments. Now with that, Craig, let me turn it over to you, and let's start the Q&A. I'm sure there must be a lot of questions from the audience.

Yes, there sure are, Cuong, and thank you for that excellent presentation. [Operator Instructions] We have many of those, Cuong. Here's the first one. You mentioned that the results allow you to have an enrichment strategy. What does that mean when designing clinical trials?

Thanks for that question. And that, of course, is a key part of what we will be focusing on now as we design the Phase III trial. Enrichment simply means we over-enroll a population that we think the drug will work for, right. So let me give you an example, and I'm just going to use round numbers. This is purely, purely hypothetical. So please do not take it for anything more than it is. So if we were to enroll 100 patients in a trial, the data that we saw here would suggest that about half of them would have the higher inflammation and about half of them will be lower inflammation. And since we know that bezisterim works faster and more -- with bigger impact for those that are in higher inflammation. And since we want to have an insurance policy to make sure that we win on Part III scores on the statistics, we would over enroll. We would, just let's say, enroll another 25 patients. with higher inflammation. And that's all it really means. We will over enroll the patients that meet the characteristics that we have here in this particular case, inflammation. I hope that answered your question.

What does the Phase III trial design look like? And will the FDA agree to that?

Sure. I somewhat alluded to that before. Let me -- Joe, let me start and then you can chime in to see and build it up. We are thinking that the agents -- the regulatory agencies, of course, are very conservative. They'd like to do the things that they have done before, right? And all Parkinson's drugs have been approved based upon motor symptoms, right? And that essentially comes down to Part III scores, sometimes Part II and III, but majority of the time, it's Part III score. So we don't want to stress or put anything at risk. So chances are we will have our primary endpoint as Part III score. But the FDA also knows that there is huge unmet need around non-motor symptoms, right? And that's been well known. In fact, the Parkinson's Foundation conducts an annual survey of their community. And every single year, non-motor symptoms comes up to be the #1 or the #2 unmet need in Parkinson's. So of course, we will go and make the argument that Part I score, Part II score, the sleep score and perhaps even EPNIC-15 should be part of our endpoints as well, right? And so those are early symptomatic endpoint for the first 6 months of the study. Notice we are extending the study from what we just did here from 3 months to 6 months. Again, that is an insurance policy to make sure that we're able to see bigger separation between those that are on placebo, and those that are on drug. Remember, it's neurodegenerative. So the longer you are on placebo the more worsening you are going to experience. And the longer you're on drug chances are the more benefit you're going to get. So even widening benefit between the groups. That's the 6-month symptomatic input that we can use to go to get approval, to seek approval. As we end the study at 6 months, that doesn't mean we stop. We will extend with those very same patients for another year, perhaps, right? And we can design it so that we can stop whenever we get the results that we won. And that the results there, of course, is to show that there is for having an impact on slowing the progression of the disease. And there are a number of different ways that, that could be shown, and that's we are working with our experts in that. So clinical trial, primary endpoint around symptoms at 6 months, extend that for another 12 months to get disease modification. And we just do not believe there would be any reasons why the FDA would disagree with that because that is a very classical design. Give them what they seek at a minimum, Part III score, give them beyond that and they would love that, and they are there to help the patient community as well. So hopefully, that answered that question. Joe, anything to add?

I think you've covered it. The wonderful thing here is you have 2 activities. You have what we've seen to be improving in symptoms. And we also have the ability to slow the disease, at least we hope so, right? That's what the biomarkers suggest. That's what this data suggests and this is what we'd have to prove in the next study.

Thank you, gentlemen. The neurodegeneration data look really interesting. What needs to be done in the Phase III to get a disease modification claim?

Yes. I think I touched on that a little bit. It's -- we would need to extend the study for 12 months or so beyond the first symptomatic relief endpoints. And the longer we extended out, we believe that there will be even greater and greater separation. We will be able to show that patients that are on treatment, one, hopefully, we'll see a benefit on the biomarkers of neurodegeneration of GFL, NfL and GFAP, right? But the FDA loves biomarkers, right? So we will absolutely track those. Then the other, of course, is what's happening to them on MDS-UPDRS parts I, II and III and EPNIC and anything else that we can show. And if there is a tight correlation between biomarkers and disease progression, that is a home run. If we could just show a change in disease modification to the trajectory over time, that is a big deal as well, right? Mark, Joe, anything to add on that?

I think in the second phase of the study the most important thing is to see the change in slope in the active study group. And so in that slide you showed where you were just treating a patient like levodopa did, you didn't see a change in slope. Patients continue to progress, but they had an improvement in symptoms. With bezisterim, you should see a change in the slope to identify disease modification.

Terrific. Thank you, Mark. Right, let's go to the next question. Craig. Craig, can you give us the next question?

Excuse me, I was muted. How can one contact the doctor doing a physician-initiated study of bezisterim?

Great question. Thank you for that. Let me first explain what -- an IIT first investigator-initiated trial. The FDA has many different kinds of clinical trials that they would consider and approve. This is -- what we just saw today is your classical what's called sponsored trial where a company would conduct a trial, right? But there are trials where a researcher can initiate himself or herself, right? So if Mark wanted to go and do a clinical trial, he can go and initiate a trial himself. And we believe that bezisterim has a much broader impact than what we, as a small company can study by ourselves. So we have put in place a program where we would support investigator-initiated trials, where if an investigator comes to us with a plausible hypothesis for how this patient could benefit from our drug, or if a patient is -- has a condition that we are studying, but doesn't qualify for a clinical trial. We could support that investigator and they would need to submit a protocol to the FDA and get authorization from the FDA. They would need to get approval or by what's called an IRB, right, that looks after safety of patients in trials. So they have to do a number of other things. But if they cross all those hurdles, we would support the trial by giving them drug, free access to drug to see if the drug works for patients. And we have done this for a number of different indications. Frankly, the first study that we did in Alzheimer's was an IIT, we have supported a trial in traumatic brain injury. Some of the early data that we have in long COVID come from IIT. With that said, there is not a simple place that you can go and look "Oh, these are the clinicians that are doing IIT." So that just doesn't happen. I can just -- at this point in time, I can just tell you that there are IITs underway are being considered in the New York Metropolitan Area. And then there's one in the San Francisco Metropolitan Area. And I believe there's one in Miami area as well. And a few are in that area -- those areas. And if you have something perhaps in Parkinson's and so forth, reach out to us, and then we will endeavor to -- we will ask those clinicians if they are open to having a conversation and if they are, we would endeavor to connect you. But that's the only way to do it. Or if you have your own -- if you have a clinician that is interested in initiating a trial, we would entertain and have that conversation as well.

If I can add something, one of the great byproducts of this Phase II trial is the company learned how to recruit patients. And you work closely with websites. You work closely with the Davis Phinney Foundation and the Parkinson's Foundation and you figured out how to recruit patients rapidly and in the right phase. You also figured out and demonstrated that patients could be seen in their homes versus traveling to long distances to be seen in an office and that's one of the more exciting pieces of data that we will look at, because I think you will prove that it is cheaper to see patients in their home, and we already figured out how to collect data. So if the questioner is worried about Parkinson's disease enrollment, you have figured that out, and it will be easy for patients to seek enrollment.

Yes. Next question. I was in the trial IIb study. What's ahead for me?

Oh, Joe, that's a hard question. I'll let Joe answer that one.