BioVie Inc. (BIVI) Earnings Call Transcript & Summary

Good morning, and welcome to the BioVie KOL investor webcast. [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. I'd now like to turn the call over to Dr. Joseph Palumbo, Chief Medical Officer of BioVie. Please go ahead.

Thank you very much, Tara. I am delighted to be with you here today on this investor webcast. I'm going to advance this next slide, and this will just bring up our -- if the slide will advance, bring up our forward-looking statements, and I think you are familiar with this, and we'll move on. So we are really delighted to have with us today 2 very distinguished scientists. First, we'll hear from our SVP of our long COVID program, Dr. Penny Markham. She'll be talking about ADDRESS-LC. When Penny is finished, we're going to be hearing from Dr. Lindsay McAlpine, who is a faculty member and neuro-immunologist at Yale University in New Haven. And she'll be speaking on long COVID and the brain. When they're both done, we'll take some participant questions. So with that, I'm going to advance to the next slide and turn this over to Dr. Markham. Thank you.

Thank you, Dr. Palumbo. Very happy to give our first presentation on our new program in Long COVID and give an overview of our clinical trial ADDRESS-LC. This is a double-blind randomized study, evaluating the safety and efficacy of our drug bezisterim in adults with long COVID. Before I begin, I want to acknowledge that this clinical study is fully funded by a grant of $13.1 million through a congressionally directed medical research program in DoD and the opinions, interpretations, conclusions, et cetera, are those of BioVie. I'm going to start with a brief overview of long COVID and neurological COVID. I'm going to talk about what people believe is current hypotheses about the causes of long COVID, talk about our drug bezisterim and its mechanism of action and then go to the design of our trial and update on current status. Next slide, please. So long COVID is broadly defined as a condition where symptoms, debilitating symptoms persist for at least 3 months following an infection with the SARS-CoV-2 virus. The most common symptoms include neurological symptoms like brain fog, fatigue, post-exertional malaise, sleep disorders. There's also -- there isn't an organ that cannot be affected post-COVID infection, and it's estimated that at least 17 million adults and 1 million children in the U.S. currently or ever had long COVID. It is a huge chronic condition, and there is currently no FDA-approved treatments, a huge unmet need. And I just want to add that there is a perception that long COVID may be going away from vaccination -- as a result of vaccination or less virulent strains of COVID circulating. This is actually not the case even though the risk has decreased from 30% to 50% in the first year of COVID, the 5% incidence rate right now translates to huge numbers when you consider that there are 3 to 4 waves of COVID a year and at the peak of these infections, 1 million are infected a day. So this year -- there can be a pipeline of long COVID patients being generated at 30,000 new patients a day. So it needs to be addressed and new treatments need to be evaluated and developed. The next slide, please. Dr. McAlpine will go into more details about neuro-COVID, which is really the neurological symptoms being suffered by these patients, 80% of patients with long COVID have some neurological symptom. And the most common are brain fog, fatigue, exertional malaise, sleep disorders, headaches, but there is -- I'm not going through the laundry list of symptoms. In 2022, neurological COVID was considered the third leading neurological condition in the United States. And the cognitive deficits in particular, appear to be related to attention, sustained attention, working memory, processing speed and psychomotor function. And as you can imagine, if you are suffering from this particular aspect of long COVID, your ability to work, concentrate, et cetera, is greatly impaired. So importantly, less than 20% of patients experienced resolution of symptoms after 12 months. Next slide, please. So what causes long COVID? There's -- beyond a doubt, there is a consensus but chronic inflammation appears to be at the crux of the pathology. What causes this chronic inflammation? There are a number of hypotheses, including persistence of virus or viral proteins or fragments, reprogramming of our innate immune cells that are pro-inflammatory and causing a kind of an increase of a population that are very aggressive and causing damage in tissues, including the brain, Autoimmunity, this is after the infection, the body's own immune system starts attacking its own cells. And there's evidence for reactivation of latent or dormant viruses, including Epstein-Barr virus and herpes. So the particular pro-inflammatory pathway that appears to be activated in -- particularly in immune cells in long COVID is what's called the TLR4 signaling, pro-inflammatory signaling cascade depicted and I must say, extremely simply on the right-hand side here. There are multiple components to this particular signaling cascade. And it's a receptor, TLR4 is a receptor on innate immune cells like macrophages that is sensing for invaders. And when it senses a foreign protein or DNA from a virus or bacteria or anything else, it gets activated. And normally, it should be activated just very transiently to up regulate the body's immune system and induce the expression of a protein NF-kappa-B to activate the production of these cytokines or immune-signaling molecules, interleukin-6, interferon-gamma and TNF-alpha, which are shown to be increased in long COVID patients. And importantly, the critical component of this pathway that is involved in potentially sustaining this inflammatory loop is a MAP kinase called ERK. And there is no increasing evidence that this pathway is particularly important in long COVID. Through proteomic studies and genetic studies, there are variants of this TLR4 signaling receptor that are associated with severe COVID and neurological COVID. What could be the main culprit here that is activating this pathway? It appears that from recent data, it could be the viral spike protein. This is a highly inflammatory protein that binds TLR4, activates the signaling pathway, it can -- it's shown to persist in the circulation of patients after an initial COVID infection. It's source is unknown. It's believed there could be a hidden viral reservoir, somewhere that is producing this protein, it can cross the blood-brain barrier, get into the brain, and it has been shown in rodent studies and some very elegant studies actually that if you inject this particular protein into the brains of mice, you will induce a cognitive dysfunction very similar to long COVID. If the mice are lacking TLR4, you do not induce this dysfunction or if you block it pharmacologically with the TLR4 inhibitor, you can also diminish the cognitive impairment. Next slide, please. So what is our drug? Bezisterim also called NE3107. If you have any biology or chemistry background, you'll see it looks like a steroid. It is actually -- it's similar to a precursor of our own natural steroids. It's a derivative of DHEA, a natural human supplement people take. This is a derivative of a metabolite and there is a long story behind the development of this molecule. It's been in development for 20 years. We have the 2 key scientists work with us at BioVie. And there was a lot of excitement about DHEA more than 20 years ago because there was incredible properties ascribed to it in rodent studies, anti-inflammatory activity and anti-aging properties. But when these studies were conducted in humans, there was no effects seen. And basically, it was because the metabolism of this molecule is different in rodents than humans. And so they were able to mimic the type of molecules that were being produced in rodents and produce a metabolically stable derivative of this metabolite and hence it's called -- this is called bezisterim. Importantly, it retains the anti-inflammatory activity that was seen in early studies in rodents. It does not get converted to sex steroid hormones or binds steroid hormone receptors. It can cross the blood-brain barrier, get into the brain, potentially to attack neuroinflammation. It's orally available. It's a capsule. And we have a good safety profile to date. It has been in over 400 participants and is well tolerated. And additionally, it is not immunosuppressive. And at least from in vitro studies, appears a low potential for drug-drug interactions. Next slide, please. So why study bezisterim in long COVID? Well, in addition to all those previous attributes I mentioned, which is what you would want to have in a drug to be able to implement it rapidly to test the hypothesis and see if it could have efficacy. It has this unique mechanism of action that appears very relevant to the pathophysiology. There are numerous publications that are all on our website and posters and presentations that show this bezisterim inhibits this TLR4 pro-inflammatory signaling cascade. And more specifically, it binds the MAP kinase ERK there that seems to be at a kind of a pivotal point in the cascade of pro-inflammation of contributing to sustaining that pro-inflammatory state. It has shown activity in models of neuroinflammation, including Parkinson's disease, glaucoma. This means that it can get into the -- cross the blood-brain barrier and attack neuroinflammation. And we have seen positive signals in clinical studies to date that may translate to long COVID and improvement in cognitive impairment in patients with MCI and Alzheimer's and improvements in fatigue and energy in patients with Parkinson's disease. Next slide, please. So when we initially started this program, we immediately engaged the advice of some key scientific advisers. These include Michael Peluso and Steven Deeks from the University of California, San Francisco. And they were -- these were really one of the first scientists to study longitudinally patients after the long-term health consequences of a COVID infection and they have one of the largest cohorts they've been studying for over 4 years. They've been involved and are involved in intervention trials in long COVID and they were able to contribute very significantly to the design and considerations for our Phase II study. Additionally, we have Dr. Sherry Chou and Igor Koralnik from Northwestern Feinberg School of Medicine in Chicago. They are experts in the neurological consequences of a COVID infection. And particularly, Sherry -- Dr. Chou has studied the neurological consequences of those being hospitalized with COVID infection. And Dr. Koralnik was one of the first to start a long COVID clinic that focused on neurological symptoms of long COVID. Next slide. We have also engaged the advice of long COVID patients who have been actively involved in any or chronic fatigue syndrome, syndrome very similar if at least 50% of long COVID patients are now being diagnosed with any ME or chronic fatigue syndrome. And these include Anisia Corona, Lisa McCorkell, Ezra Spier, Chimére Sweeney and Angela Vazquez and they are all involved in different aspects of creating awareness, obviously, patient advocacy, providing websites for patients with the ongoing studies that are actively recruiting and also involved in patient-led research that has contributed significantly to our understanding of long COVID. Next slide. So our Phase II study is a double-blind randomized study. We're going to enroll 208 participants. They will have an equal chance 1:1 of getting randomized to placebo capsule or bezisterim, the drug. We're looking at 18 clinical sites. And the trial is registered on clinicaltrials.gov and we also have a trial website addresslc.com that we will be updating with -- as sites get activated and they are recruiting, we will be updating locations and contacts, if anyone needs additional information. And there are also more detailed information on inclusion and exclusion. Next slide. So the design, it's an up to 20-week commitment for a patient or a participant. There is a screening period of up to 4 weeks where we will assess eligibility. And those that are found eligible will come to a baseline visit where they will be randomized to either our drug capsule, which they will take twice a day or placebo capsule, identical matching placebo capsule, they will take twice a day. There will be monthly site visits during the 12-week treatment period, where there will be assessments for safety and efficacy. And the final visit will be the final assessment for efficacy after 12 weeks. And there will be a 1 month after the end of treatment, there will be a virtual visit just to assess for safety. Next slide. So to maximize the signal detection in this population, we are enriching for both cognitive impairment and fatigue. We will have key inclusion criteria that will require the patient to have both objective cognitive impairment and perceived cognitive impairment or patient-reported cognitive impairment. We're also requiring patient-reported fatigue. And for this first signal-seeking study, we are limiting enrollment to those who have experienced symptoms for up to 2 years from the inciting or suspected COVID infection. Key exclusion criteria are very important in the study because long COVID is a diagnosis of exclusion. So it will include any lab abnormalities, infections or neurologic or psychiatric conditions that can account for the cognitive dysfunction or the other causes of fatigue. And we will also confirm eligibility by an internal BioVie enrollment authorization committee. Next slide, please. So the outcomes we're looking at, at the end of treatment or cognition, both objective and subjective and our objective measure is a bespoke cog state, cognitive battery, where we have selected the cognitive domains that we want to test that have been reported to be most impacted in patients with neurological dysfunction or brain fog due to long COVID. We're also looking at perceived cognitive function, fatigue post-exertional malaise, sleep disturbances, overall health-related quality of life, a clinical change from the perspective of both the clinician and the patient severity and change of symptoms over 400 biomarkers of inflammation and neurodegeneration will be evaluated and particularly, excited about the inclusion also of evaluation of changes in epigenetics or methylation of DNA in these patients. We have a very exciting paper that's just accepted for publication in Frontiers in Neuroscience that's reporting on these epigenetic changes we saw in placebo-treated patients versus bezisterim-treated patients in a subset of participants in our MCI and Alzheimer's study. Obviously, importantly, we're also looking at the safety and tolerability of the drug in this new long COVID population. Next slide. So the current status, we're extremely busy activating sites. Patient enrollment is imminent and is anticipated this quarter, and the top line data is expected in the first half of next year 2026. So thank you. I am going to pass to Dr. McAlpine.

All right. Can you see me and hear me appropriately?

Yes, we can.

Okay. Great. So thank you for having me today. I'm Lindsay McAlpine. I'm neuro-immunologist and neuroinfectious disease specialist at Yale. I'm also a physician scientist funded by the NIH. I just started a neuro-COVID clinic at Yale back in 2020 with my mentor. And I quickly noticed that my patient sounded sometimes like they were reading from a script, their stories and symptoms were so similar. Then I realize that there was a real pathology here. They were fine before COVID. And afterwards, they could no longer live the lives that they had and in many more ways than what physically cognitively and emotionally. So my research and being here today is motivated by my patients and everyone affected by this disabling disease and to bring awareness to the problem, the disease pathways and expedite treatment development. So I have no relevant conflicts of interest. I don't have any financial holdings or interest in any pharmaceutical companies, including BioVie. I am a principal investigator of a bezisterim clinical trial site at Yale, and I'm funded by NINDS in the NIH. So here's an outline of what I'll be talking about today. The problem, pretty typical patient case, about long COVID in the nervous system, specifically, the hypotheses we have and then our study at Yale. And lastly, why I think bezisterim is a compelling therapeutic. So long COVID has been proven over and over again to be an enormous problem across the world. Nature Medicine has estimated over 400 million people have developed long COVID at some point with an annual global cost of over $1 trillion. Harvard has broken this out by loss of quality of life, lost earnings, additional medical expenses. And then currently, there are about 20 million Americans suffering from long COVID currently. It's currently incurable and there are no FDA treatments. So it really is an enormous opportunity. For some perspective, I included the prevalence of other neurologic infectious diseases, Alzheimer's disease affects 6.7 million, HIV 1.2 million and MS, my other subspecialty, 1 million people in the U.S. So we have done wonders in the medical community to lower the risk of developing long COVID, anything that reduces the viral load or the length of viral -- active viral replication during the acute infection can reduce the risk of developing long COVID. So this includes vaccines and antivirals. However, unfortunately, both at present are being significantly underutilized in our communities, the uptake of the last booster was lackluster at best. And many seemingly healthy patients are not offered or even denied antiviral treatment during their acute COVID infection. But they're really still risk for long COVID, high-risk factors include recurrent infections, which are not going anywhere, female sex, obesity, lung disease, diabetes, and hypertension, all of which are prevalent in the U.S. So everyone asked me, aren't you running out of patients? I wish. The answer is, absolutely not. My clinic is booked almost to 2026. And this last December, we are still having many, many infections like Penny mentioned, anywhere upwards of 300,000 cases of COVID a day in December of 2024, just our last December. And the vast majority of people in the U.S. are at high risk of long COVID, female, obese, and/or have hypertension. And they're on their second, third, fourth COVID infection. So long COVID does not discriminate by race, ethnicity or socioeconomic status, patients or people just like you and me. There's a lot of health care workers in our clinic. And here's a case of one of my patients. At the time of contracting COVID, she was a healthy 45-year-old woman with hypothyroidism and seasonal allergies. She presented to my clinic 9 months after her illness with severe activity and exercise intolerance, fatigue and cognitive dysfunction. She's a Yale professor, and previously was an avid runner. She got COVID from her school-aged children and was sick at home for a while, longer than the rest of her family about 3 weeks. And she really feels like she never fully recovered. She tried jogging a mile about a month after her COVID illness and was bed bound for 3 days afterwards. This is what we call a crash. So she tried to return to teaching, but had substantial difficulty speaking fluently during lectures, keeping track of her thoughts, tasks and recalling basic ins and outs of her job. Since COVID, she has not improved and is on medical disability leave from her dream job. So what can we do for her? Right now, we don't have anything really. So how does long COVID affect the nervous system? Here's a diagram, a variety of neuropsychiatric symptoms. I often describe it to my patients as, if all the things in your body that your body does autonomically or automatically that we take for granted and it all goes haywire. So anywhere there's a vessel or an autonomic nerve, there's a symptom. So thinking, concentrating, sleeping, balance, standing up, bowel movements, bladder function, sweating, the ability to have an appropriate response to exerting yourself, like climbing a flight of stairs. The symptoms are pretty far reaching from headaches to numb feet. So based on current literature and learning from my hundreds of patients that I've seen, we have several hypotheses that we're looking into for long COVID. They include neuroinflammation, direct autoimmune attack, viral persistence, vascular, neurovascular dysfunction, injury to the brain and contributions from predisposed susceptibility. So I'll be focusing on these 2 today. So the inflammation in acute COVID is dramatic and profound. Over the last 5 years, we've really come to have a pretty good understanding of what happens, and I'll highlight some mechanisms that are relevant to bezisterim today. So in the brain autopsy studies, we found that there's significant inflammation in the brain and activation of the microglia, which are the innate immune cells in the brain like innate macrophages. So I will -- let's see. There is significant and severe inflammatory storm with elevated immune cytokines like TNF alpha, interleukins and interferons and this can disrupt the blood brain barrier. Spike protein itself stimulates toll-like receptor 4 nuclear factor kappa beta pathways fueling the storm and activation of these pathways has been linked to cognitive impairment in animal studies and endothelial inflammation. And the endothelium lines every single vessel in the body and is critical to the long COVID story as well. So inflammation in long COVID is more subtle, but has been documented and reproduced over and over again across the world. Microglia play a fundamental role in the innate immunity and plasticity in the brain. A study out of Canada demonstrated activation of these immune cells in the brain, in the deep gray matter structures in long COVID, a [new] study into the gene pathway showed NF kappa beta activation was leading to smoldering pro-inflammatory cytokine signaling. And specifically in this pathway, a study from Yale and Stanford showed that CCL11 leads to microglia activity and myelin loss. So next, I'll be talking about our study here at Yale. We've been working on this since 2020 to understand how long COVID affects the nervous system. And we've been capitalizing on tools used in central nervous system studies for many years. So to date, we've enrolled over 50 individuals with long COVID and over 30 controls, and we're still recruiting. We don't have thousands of patients like recover, but we phenotype our participants very deeply. So they get a blood draw that goes into a repository, 3 hours of neuropsychological testing, a lumbar puncture with spinal fluid that goes to repository. And then if they have cognitive dysfunction, they get a 3T MRI with and without gadolinium contrast. And then we perform the appropriate analysis. So here's a brief look at our study population. They're majority female, majority middle aged, and they were mostly ill at home. And there are no differences between the groups in terms of age, gender, race and vascular risk factors. Our participants report typical long covid symptoms. There are many that affect the neuropsychiatric access including fatigue, post exertional malaise, poor concentration, word finding difficulty, poor memory, mood changes, muscle weakness. So on cognitive testing, this is our preliminary data, and we found that our participants demonstrate deficits in verbal memory and processing speed. On the left in red is long COVID, on the right in blue is our recovered controls. So they all had COVID, but recovered fully. Learning and fluency was normal. And as expected, in many neurologic conditions, they also reported increased anxiety and depression. So given other groups have demonstrated microglial activation in long COVID, I wanted to explore the spinal fluid deeply for any alteration. So we sent 70 of our samples to Olink for high-throughput CSF proteomics. So they studied -- we studied 5,400 proteins and 4 of them stood out. So they involve cell fade and regulation of cell growth, cytokine and growth factor signaling. And lastly, inhibiting innate immune response to viral infections. So these are all highly relevant to long COVID, and I look forward to expanding our analysis into this. So next, early in the pandemic, I published a paper on inflammation of the endothelium, vessel lining, in patients with acute stroke and acute COVID. So I was really interested to look into whether, this type of inflammation was present in long COVID. So I found elevations in kind of nonspecific acute phase proteins as well as biomarkers of atherosclerosis. And this is more than 2 years after onset of long COVID. And then interestingly, I also found elevated biomarkers of endothelial inflammation, especially those that involve white blood cell adhesion to the endothelium. So it's really -- we're finding this at the intersection of the vasculature and the immune system. So -- and then lastly, we found elevations in 2 neuronal biomarkers, pTau, a marker of neuronal damage and then GFAP, which is a key marker of astrocyte activation, which is at the blood-brain barrier, typically. Next, I wanted to look at the actual brain. So I did an analysis of our MRI data measuring volumes of different brain regions, particularly the gray matter cortex on the outside. And I was -- I looked at the white matter as well and was surprised to find no difference between small punctate white matter lesions between groups. But I did find decreased gray matter volume in areas aligning with the cognitive scores and reported symptoms that we've seen. So isthmus is reduced in volume, and this is critical to emotional regulation as well as memory, pain and cognitive processing. The [ OTO ], which is known as Broca's area, is reduced and involved in critical to speech production and semantic language, so the meaning of words and language. And then lastly, the bilateral parietal lobes are reduced. And these are really critical to a lot of integrating functions such as language, attention and working memory. So based on preliminary data showing reduced blood flow to the brain on ultrasound, and also my findings in the blood, I wondered if blood flow related to our gray matter finding. So I looked at arterial spin labeling MRI, which measures blood flow perfusion in the brain. And it showed a decrease in blood flow in several areas, which are in red. And these areas directly overlap with the reduced gray matter in the parietal lobes seen on the last slide. So why is this happening? This area is vascularly vulnerable. It's located at the intersection of 3 major arteries in the brain, the anterior, posterior and middle cerebral arteries, you can kind of see it right here. So to me, these findings make sense because we know that there's dysautonomia or dysfunction of the blood vessels in the autonomic nervous system throughout the body. And so the fact that it's happening in the brain as well as important to document. So now I've gotten to the meat of the presentation, why bezisterim? So it really does have an ideal mechanism of action. All the antiviral studies unfortunately have been negative so far. So we know there's inflammation in this condition, I would say about 2/3 of my patients either have another autoimmune disease or they have a positive antinuclear antibody showing a tendency towards inflammation and autoimmunity. So we need trials with compelling therapies with anti-inflammatory mechanisms. So bezisterim is a derivative of DHEA and reduces inflammation with -- through a lot of the mechanisms I've talked about today. And the safety profile is excellent. A lot of my patients would probably take on quite a bit of risk in terms of taking a medication to provide benefit. And here, we're lucky, it's actually quite safe. Additionally, I strongly agree with their rigorous study design and the rigorous inclusion and exclusion criteria. Given these preliminary studies and the sample size, we really need homogenous cohort to effectively find a signal of present. We really want to avoid a false negative study. And so we have to be a little more stringent in order to have benefit after the study. So I think it's very well designed. And it's really wonderful that we have proven outcomes. So especially related to direct symptoms and measures that are relevant to long COVID. And so there was increased blood flow on perfusion imaging in Alzheimer's disease. There was improved objective cognitive function in early mild cognitive impairment. And there was also those tau levels that were elevated in the blood of long-COVID, those were reduced in the spinal fluid, people taking bezisterim in Alzheimer's studies. And then lastly, in Parkinson's, which interestingly shares something very similar with long COVID is, it has a high prevalence of small fiber neuropathy, again, that dysfunction of autonomic nerves and it improves fatigue in Parkinson's. So that's quite compelling that there might be an effect in long COVID as well. And then lastly, there are no studies looking at the vascular effect of bezisterim in humans, but DHEA, the parent molecule shows -- has been shown to have an anti-inflammatory effect in the vessels, including prohibiting -- inhibiting vascular proliferation and white blood cell recruitment. So really these are the ideal outcomes for long COVID. And I would say that the fatigue and the cognitive function are some of the most debilitating symptoms and conditions in long COVID that I see. So I also have a sub-study planned, so I applied for internal funding to do a parallel sub-study on participants, which I'm very excited about. So the first task is I hope to do task-based functional MRI imaging, both before and after therapy to assess for improved or altered cognitive function. Aim two, looking at perfusion. So we know perfusion is an issue in long COVID. We know perfusion increases in mild-cognitive impairment. How will it change in long COVID? So I'm excited to look at that. And then lastly, looking at those vascular neuronal neuro relevant biomarkers and whether bezisterim can move the needle there as well. So very exciting. So acknowledgments. Good research takes a village, takes a lot of collaboration, and it takes time. So I'm grateful to all those who have contributed, to all of our participants who have joined and altruistically, gotten lumbar punctures and unconfortable MRIs so far. We're very grateful. So now we can hand it off for questions.

Great. Thank you, Dr. McAlpine. So I'll now turn the call over to Bruce Mackle from LifeSci Advisors to read any written questions that came from the webcast.

Thank you, Tara. We have a number of questions here. So first one, what role do you attribute the SARS-CoV-2 spike protein S1 contributes to fatigue and neurocognitive impairment. Will you be testing for S1 antibodies? And is it possible that bezisterim will eliminate the spike proteins?

So I think Dr. McAlpine can address part of that and Markham can follow up on biomarkers.

So I think Penny hit on it. Right now, in my research, we're looking at the underlying mechanisms and spike protein certainly can be a stimulus. I think there's been a lot of focus on it, but there's also through Dr. [ Peluso's ] work and others that it may be viral RNA or persistent viral antigen that's also stimulating this smoldering inflammation. So I don't think we have an answer to that yet. But it certainly plays a role in stimulating the immune system during acute COVID and whether it's persistent in long COVID, I think remains to be seen broadly.

And just to add, we are not assaying for spike protein. There really is no validated assay. There is a group that has a sensitive enough assay to detect it. But we currently have no plans to add that.

The next question, how was BioVie learning from failures of other long COVID trials?

Markham?

Yes, there's a lot of information to be gained. We have taken a very stringent enrollment approach for this first study. It's a signal-seeking study. We are enriching patients for, we believe, the symptoms that are drug can most impact based on its mechanism of action. Previous studies have not been as stringent or requiring both cognitive and subjective impairment and fatigue. We think we'll get a -- it is a heterogeneous population, but we think we will enrich our signal greatly by our approach also with our limitations on age. We are eliminating the potential complexity of MCI in an older population by limiting the age to 65. And also limiting to those patients who are only -- have only experienced symptoms for up to 2 years. We believe in this window, we have the best chance to move the needle. And so we have learned a lot. I mean -- we're fortunate that we are kind of at this stage because it has been a rapidly evolving condition or syndrome, where scientific data continues to come out and the learnings. And we have been able to use those learnings, I hope to our advantage.

Dr. McAlpine, I saw you nodding your head. Did you want to add to anything?

Yes. I think it's important to emphasize the signal finding aspect of the study. And then that gives us so much more power to widen the treatment group after.

[Operator Instructions] We do have a question here from Tyler Bussian from Brookline.

It's been a great presentation. So I actually have questions for both Dr. Markham and Dr. McAlpine. Let's start with Dr. McAlpine. So specifically in your current studies, you noted an elevation of phospho tau, can you talk a little bit about what isoform you identified being elevated -- for those patients...

Yes, that's a great question. It was total tau. And we're in the process of sending more repository samples to kind of tease that out.

Got it. So total tau, not specific isoform of total Phosphorylated tau?

Correct.

Okay. Got it. Now I want to quickly ask you also, Dr. McAlpine because your experience in this field is interesting and it is a very new field. I've seen a lot of literature suggesting different proposed subtypes of long COVID. Those with the neurological conditions, those more fibromyalgia kind of conditions, neuropathy like styles. So how does that type of, I guess, kind of compartmentalization or kind of the potential subgrouping impact this trial? And how do you actually think about that in terms of this pathology?

So that's a great question. Fibromyalgia as a diagnosis is really turning into small fiber neuropathy. We're finding that, that's present in a lot of patients. With fibromyalgia and one of the tricky things about long COVID, and specifically the neuropathy component is that 95% of small fiber before COVID was length dependent. And our testing right now is the skin biopsy based on that length-dependent mechanism. About, I would say, more than half of the patients I see with small fiber neuropathy when we're able to catch it is non-length dependent, it's patchy. And so that, like length dependent skin biopsy is not really the ideal diagnosis technique. And so I feel like we're missing a lot of it in our long COVID patients. We know that small fiber neuropathy, chronic fatigue, POTS, all of those things can often overlap, but it's not 100%. So I think that's something that we really hope to learn more about through COVID and long-COVID is why is it not 100%, right? So we know chronic fatigue syndrome involves dysfunction of the autonomic nervous system. And that can align like POTS with small fiber dysfunction because the small fibers are in the bowel, they're in the vessels. They're in the bladder, they're in the skin, they're controlling sweating and all of the regulatory functions, but why can't we find that in everyone. So does that answer your question?

I think a little bit. Yes. I mean, there's obviously a lot of questions developing...

There's complexity. Yes. I think that's, again, why it's important in this study to include individuals. I usually in my clinic, think about individuals with post-exertional malaise and without. And that's really main dividing feature of my patients. And so I think focusing more on those with post-exertional malaise, will be able to get us a more homogenous group.

Fantastic. And Dr. McAlpine and Dr. Markham and kind of the rest of the BioVie team, I mean kind of going off of that for a little bit. Obviously, you're looking at very strong exclusion criteria, utilizing both subjective and objective cognitive measures along with fatigue. But there's a very likely chance that this patient group that you look at might be diverted or might be subgroups within it. So you haven't planned kind of sort of prespecified subgroup analysis you're going to plan to look at post-Phase II, which might be informative for a Phase III program?

Absolutely. We will be looking in a lot of prespecified subgroup analysis. We are stratifying by age. We will obviously be looking at correlation of changes in our biomarkers, the neuroinflammatory -- inflammatory I should say, and markers of neurodegeneration. We'll also be looking at changes in epigenetics, we'll be correlating. We have a number of different PRO measures and domains of certain measures like the SF-12 quality of life. We'll be able to use those as anchors to corroborate any efficacy we see. And it's -- we plan to hone in and see where the subgroup that is most responsive and whether it be going forward that we -- there's age, sex, we will be looking at multiple parameters to see where the best signal is seen.

Got it. And do you plan to do those both, just I mean the pre and the post phase for patients? Or would you like to also do interim every X number of weeks to get a more of a longitudinal effect of bezisterim on patient outcomes?

Yes. We will be looking at the data, obviously after 1, 2, 3 months. Our endpoint, really, our outcomes are looking after 3 months of treatment, but we will be able to look exploratory analysis into changes at those earlier time points. I'm sorry -- go ahead.

Go ahead.

It is little too early -- sorry...

I would argue that this is a subgroup, right, in of itself, like we are isolating for people with objective cognitive dysfunction, impairment and fatigue, post-exertional malaise. And so that, in my experience, yes, there's some -- there's a spectrum there. Some people get a little more cognitive fatigue, more physical fatigue. There are crash levels in different places. But really, it's the same syndrome.

And the next question we have here is, how effective is your drug for long COVID patients?

Well, Markham?

We will not know until the results of this study.

Purpose of the study.

Next question, will there be separate groups evaluated based on whether or not participants took the mRNA vaccine?

No.

Next question, can bezisterim also be trialed to treat ME/CFS from COVID or from other illnesses like EBV HPV?

Both Dr. McAlpine and Dr. Markham.

We would love to. We hope to get a positive signal from this study. And obviously, there is a tremendous overlap in those conditions, genetic associations. There is an overlap of TLR4, for example, in ME and CFS, and we would love to have the opportunity to test the drug in other subpopulations. And most importantly, in the long haulers, those who have now experienced the condition for at least 4 years, I have a first cousin with ME, which is why we kind of knew what it is, how debilitating these conditions are and how alarming it was that this signal initially came out in 2021. So would love to do a decentralized trial and get that drug to those people who obviously would be precluded from attending site visits in-person.Funding dependent.

Yes, absolutely. I think all of the long COVID researchers, I know we all have ME/CFS ever present, right? And so we're hoping that whatever work we do, we can then -- like this is the first step in long COVID. And then the next step is applying that to other post infectious syndromes, absolutely.

Great. The next question, whether it is RNA or antigen, if viral persistence is not addressed? I would think any improvement seen in your study would be temporary. Wouldn't a combination with antivirals be needed?

So that is a fantastic question. If you look closely at Dr. Peluso's work, you'll see that all those with long COVID don't have persistent antigen. And so I think it will end up being a subgroup that have persistent viral antigen. And the issue with antivirals is that they target replicating virus. They don't target the actual antigen, right? So they're not -- without replicating virus, the antivirals aren't necessarily going to be effective. And so we need better ways to improve the function of patients' immune systems to clear it themselves almost. So in the first round of vaccines, I had a lot of patients get better from long COVID after the vaccine, and we call that therapeutic vaccination. And that was a way that we could help their immune systems to clear that on their own is my hypothesis. And so how do we do that here? And so we know that individuals with long COVID, they have immune dysfunction. So they're not switching from IgM to IgG is effectively, they're having long periods of viral replication, and they have exhausted T cells. So targeting these maybe maladaptive persistent immune pathways can help patients have a healthier immune system. That's what we hope. So does that make it clear? I don't know, Penny, you can add on.

So just adding the persisting virus is one hypothesis. There is strong evidence that there is an epigenetically reprogrammed lineage of monocytes that are just aggressive. They're overstimulated, and they're going around causing damage. And this is believed to be driven by acute inflammation, probably during the initial infection and potentially our drug because it is showing these interesting impacts on DNA methylation and epigenetic modifications, just maybe, just maybe it could reprogram this lineage or exhaust from the systems.

Thank you both. Next question, what effect will a negative outcome of this long COVID study you have on any 3107 trials for Alzheimer's and Parkinson's?

Yes. So I'll take that. This is an exploratory study. This is a signal-finding study. So this is specific to long COVID and really not related to the other development programs. So I wouldn't see that affecting those programs.

Thank you. Next question I'm curious about your thoughts about the overlap in neurological symptoms between long COVID and Ehlers-Danlos syndrome patients?

Dr. Markham and Dr. McAlpine, I know we've actually had this conversation.

Lindsay, do you want to start?

Yes, sure. Absolutely. I think I think there was a study out of UCSF that didn't find a lot of Ehlers-Danlos in long COVID, but I certainly know in my cohort, there is quite a bit of overlap. And I think that -- I think that was on my hypothesis slide. It really is something I consider as a predisposing condition towards long COVID ME/CFS autonomic dysfunction. I don't think we understand completely the mechanism of that. But absolutely, I see a high prevalence of it of EDS in my clinic.

And all I'm going to add is we're not excluding ED in our study. So we will naturally be evaluating those patients as well.

Great. Thank you very much. Really appreciate all of your questions. I think we're going to wrap it up here. And with that, I will turn it back over to Joseph Palumbo.

Well, thank you, everyone, for your time. Really great participation, great questions. And we'll continue to advise you as this program enrolls and continues. We will be at the conferences and presenting our data. If you are interested in listening to this program again within 24 hours, we will post this. And if you follow the link for this original broadcast, that should put you to the recorded version. So again, we thank you for your interest. And with there, we'll stop. Thank you.