Before we begin, I'm required to remind attendees to please refer to the event calendar, published research, or Baird's website for important disclosures regarding the companies discussed during this event. I'll now hand it over to Joel to kick off the discussion with INmune Bio. Great. Thanks, Mike, and thanks to the INmune Bio team and Dr. Tansey for joining us today. You know, really excited to have this discussion. There's a lot to talk about on INmune Bio, but given that we have both management and Dr. Tansey here, it's probably a great opportunity to really dive into XPro as it relates to Alzheimer's disease. So I guess to begin, before we get into the details of XPro, just like to begin by throwing a question out there. What do we know about the impact that TNF inhibitors can have on Alzheimer's disease? Yeah, that's an excellent question, and we know from a lot of epidemiological studies and medical records, millions of medical records, that if you have individuals that have chronic inflammation, such as rheumatoid arthritis, psoriasis, these autoimmune conditions that start early in life, if they get on anti-TNF drugs, their risk for developing Alzheimer's and dementia really drops precipitously. So by having chronic inflammation, it's a risk factor that it increases by eightfold relative to the general population. But if you get on these anti-TNF biologics that are non-selective and will immunosuppress you, but will get rid of the inflammation, then as a group, their risk drops precipitously. So that tells us that taking TNF out of the equation is a way to mitigate the chronic inflammation and protect your brain. Got it. And maybe on that point, do you have any sense if it tends to be all anti-TNF drugs that have that effect, or are there individual drugs that seem to behave a little bit stronger of that effect than others as it relates to reducing the incidence of Alzheimer's disease? Yeah, there are some studies that show that NSAIDs, and specifically ibuprofen, can have similar effects in both reducing the risk for Parkinson's and Alzheimer's. However, the timing of those is really important. So there are studies that suggest that NSAIDs may be protective, but only if they're taking for chronic sports injuries, like tennis elbow and things like that, early in life. Studies that show no protection of ibuprofen are those where individuals are taking them right before hip replacement. So I think the timing of the intervention in terms of inflammation will matter. Yeah, and Joel, if I can jump in, and I'm gonna throw a question to CJ here, is CJ likes to say when we're talking with people, "It's not treating inflammation that's important, it's how you treat inflammation." And maybe, CJ, you can expand on that a bit. Yeah. Thanks, R.J., and hi, everybody. Thanks for joining. So it's pretty interesting. One of the things that... So I just want to say, full disclosure, I worked with Malu. My experience with this drug came from working with Malu, and really, when I was working with Malu, and we were trying to understand these mechanisms, what was very clear was that this drug was very different. It was qualitatively different. And anybody that's ever worked in a lab understands that, you know, when you're running these experiments with new therapies, sometimes you have to do a rain dance. You have to use a certain reagent. You know, only the most experienced people can do it. That's just not the case with this drug. And that sort of segues into your question, R.J., you know, why is this drug so unique, and why is it important how you target the immune system? So turns out the immune system is kind of like a Jekyll and Hyde. It does good and bad things, and sometimes even within the same target. So TNF itself is actually two different molecules. One of them is neuroprotective, and it provides maintenance and repair to the body, and the other one causes all the stuff that we think about with chronic inflammation. Now, it turns out, if you block neuroinflammation, like Malu suggested, you can reduce the risk. But what's interesting is if you look at people that have been on TNF inhibitors for a period of time, what you see is a reduction in the risk of Alzheimer's disease, but you start seeing an increase in the risk of other things, like cancer, late life multiple sclerosis, because what's happening is those drugs are blocking both that good and bad, and when that happens, you suppress the repair and the homeostatic mechanisms. That is critical to having a drug that works really well, especially when it comes to CNS disease. And one of the ways I like to think about this is neurons in your brain, they're kind of like infants. They can't really... You know, they can't do anything by themselves. They can't socialize, meaning they can't connect with other neurons. They can't clean themselves, they can't take out the trash, they can't do anything without parents, and that's what the glia are in the brain. The glia provide all that infrastructure and support so that the neurons can thrive. And so when you think about therapies targeting inflammation and the non-selective TNF inhibitors that we're talking about, that target both the good and bad, yeah, you reduce the risk of inflammation, but you also suppress the immune cells in the brain, and that's a complete non-starter for a therapy that's going to be effective. Terrific. Great. Yeah, so really, an intriguing overview of the role that neuroinflammation and, and TNF has in Alzheimer's disease. And maybe with that, let's dive in more directly to XPro, and I, I think this could be a, a unique opportunity to go all the way back to the very beginning of XPro when it was discovered, because we have Dr. Tansey here, who was at Xencor, I, I, I believe the head of Chemical Genetics group at the time of the discovery. So can you tell us more about just the whole discovery of XPro at the time? Yeah, sure. So in 2001, when I joined Xencor, there was a project that was specifically, you know, biology-based, which was to design the next generation TNF inhibitor. And it was basically done in a way that you would create a molecule, a biologic, that was able to act as what we call a dominant negative, which is that it interferes with selectively with the molecule that you have in your body. And so this is basically the approach that was taken to design a TNF molecule that would not bind receptors, but would interact with the body's own TNF and would selectively neutralize it. And so it was put through the Protein Design Automation platform. The libraries were made for the various TNF mutants. The protein chemists made the proteins. We, in my group, were in charge of making sure that these new and improved proteins or TNF mutants were really dead and would neutralize the normal TNF. And initially, we were not aware that the mechanism of action was going to selectively do the soluble TNF, but it turned out to be a really good feature or property of this mechanism of action, because as CJ said, you don't interfere with the good TNF that is anchored to the membrane of cells, that's the one that protects you against infection and promotes myelination. This dominant negative TNF, now XPro, is basically a selective soluble TNF inhibitor, and it spares the membrane-bound or good TNF, and it lowers the soluble TNF-dependent mechanism, so it quenches inflammation without the immunosuppression or demyelinating effects that some of the non-selective TNF inhibitors have. Yeah, and if I can jump in here, one of the interesting things, and Malu alluded to it, was they invented something that they didn't really know they had, right? They ended up with this drug, thinking they were gonna be treating rheumatoid arthritis, and they ended up with a drug that was purpose-built for the brain. Full stop. I mean, it is the perfect drug to treat neuroinflammation of the brain, and it's so different from all the other TNF inhibitors out there or all the other anti-inflammatory, anti-neuroinflammatory strategies. That's really what we get excited about. And once again, it was an accident. To the credit of Malu Tansey, she recognized that opportunity and left industry and went back to academia, and that's what she's been doing for the last 20-plus years, is studying neuroinflammation and TNF in the brain, so. Yeah, that's actually correct. When I left to go back to academia, I took the dominant negative TNF as a research tool to put it in various models of brain injury. And the CEO of Xencor was, "What do you mean, inflammation in the brain?" I said, "I think it's going to be really important in neurodegenerative disease." But in 2002, that was not. There was very little traction for those ideas, in part because it was thought that inflammation was a by-product of neurodegeneration. And now we really know that the immune system, those professional vacuum cleaners that clean up things that, you know, CJ explained, they are really important to prevent all this plaque accumulation. And so we think of the immune system as the first responder. So by targeting the soluble TNF-dependent effects, you can actually protect the brain, and it's not that the aggregates don't matter, but that you have to think of the diseases as immunological diseases of aging, so that you can use innovative approaches to protect the brain. Okay, so this has been a lot of interesting stuff on the mechanism of action. Anyone else have anything to add on the mechanism of action? Otherwise, we can jump into the phase I clinical data. So let me... Can I add one thing to this? Because I think this is the uniqueness and the precision of how the drug works is really important. It's not that the drug is promoting... We're not stimulating something to heal. What we're doing is we're stopping a cycle, and when you stop that cycle, the immune system can polarize itself towards being to repairing and maintaining. And as we, you know, say in medicine all the time, the best situation is to get the body to heal itself, and that's exactly what this drug does. So you... The response, the immune response is not because we forced it in a direction, it's because it's responding to the environment that it sees, and it's repairing, and it's maintaining. I think that's really critical, and one of the unique aspects of this drug. Terrific. So, you know, certainly seems like a great hypothesis to test, and fortunately, we, INmune Bio was able to do so in a phase I clinical trial. Could you tell us more about what you learned in phase I? Yes. So what was really, what's really wonderful about this drug and really Malu has all the credit for this, and Xencor as well, is it was designed, you know, long enough ago, and it was given out to researchers throughout the world to test it in any way they wanted. And I think at this point we have about 82 or 83 preclinical published studies with this drug. Except for maybe four of those, none of them were funded by the company. It was really given to whomever. So that sort of independent verification is really important. And as it relates to the Phase I study, we have the luxury of understanding the biology in such an important way across 24 different diseases, you know, maybe 60%-70% within the CNS. We know how the drug preclinically works in rodents, and we can design a Phase I study that sort of mimics that, in the sense that we know what biology to look for, we know what elements to look for to tell us if the drug is acting the way we expect it to act. So some of our biomarkers that we use may be a little different than what's typically used, but our philosophy is, is you need to be looking at mechanisms that are unique to, or endpoints, measures that are unique to how your drug works. So we designed this three-month study where we looked at inflammation in a variety of different modes and methods. When you're doing a small Phase I study, you don't have the luxury of, of, you know, large numbers, so you need to convince yourself in different ways. And one of the ways to do that is to show similarity in response across multiple different measures. So we're not relying on a single cytokine, for example, an inflammatory factor or just protein. We're looking at protein measured different ways in the brain, but we're also using novel imaging techniques that infer on inflammation. And two things that came out of that study. Number one, the drug worked exactly as we would have expected it to work. What we saw is a global shift in how the inflammatory markers moved following three months of treatment. And more importantly, one of the things we did is we did a proteomic analysis. Now, I'm not typically a big fan of proteomic analyses, especially unbiased proteomic analyses, but if you've got 80 publications with a drug and you understand the pathways and how it works, the proteomic analysis is actually really useful because it will tell you if what you're seeing in rodents is translating to humans. I can tell you that the day that I received that proteomic report, that final report, was probably the most memorable day that I've had here, because it read exactly like every single preclinical study that we've done, and I think that's really important. First thing that we learned was the drug appears to translate very well from rodents to humans. It modulated neuroinflammation in the brain. We identified the appropriate dose moving forward. There was a dose response associated with that, so we were able to identify the dose. But we also got some really interesting results that were somewhat unintended. So typical Alzheimer's studies will enrich for or select patients based on stage of disease, either MCI, mild, moderate, or severe. One of the things that we didn't do was restrict it to that group. We did enrich them based on inflammation. I'll talk about that in a moment. But one of the interesting things was, what we were able to see was some of the clinical evaluations that we did, we were able to show, that there were certain metrics that appeared to change in patients that were more mild. But we didn't see that in the moderate patients. Interestingly, regardless of whether they were mild, moderate, or severe, we saw biological changes in the brain. So we knew that the drug was having an effect on the biology, but at some point, the patient's biology has... they're too far gone. So even when you're recovering a little bit of the biology, there's not enough there to deal with the symptoms. They still have those symptoms. So it allowed us to identify where we wanna cut off our Phase II study. The other thing that's important is we're enriching for patients that have inflammation. Our philosophy is pretty simple: If you're targeting inflammation, the patient should have some evidence of inflammation. So we used biomarkers to select those patients. We actually used peripheral biomarkers to select those patients. One of the other interesting outcomes is that when we compare the patients that we selected in our trial based on those inflammatory biomarkers, and we compared that to a large database of Alzheimer's patients and looked at neuroinflammation in the brain, those biomarkers accurately identified patients that had very high levels of inflammation. Not only did we demonstrate that we could reduce inflammation across multiple modalities, we identified the dose, we were able to figure out which patient cohort we need to go after in the Phase II, and we confirmed the fact that our biomarkers, which are very easy to collect, were able to accurately identify patients that had neuroinflammation. I would say for a Phase I study, that was an incredible amount of information that we were able to glean that helped us design the Phase II. R.J., I think you're on mute. Thank you. I wanna underline four points or five points that CJ made. Number one, we had target engagement. We definitely decreased neuroinflammation, no matter how we measured it. ... Number two, the downstream benefits of decreasing neuroinflammation included improved or less nerve cell death, less neurodegeneration with improved axonal function, improved synaptic function, and also we saw remyelination. And in the patients, although it was small and not controlled, several patients actually showed improvement. So as CJ said, we couldn't have hoped for a better outcome, and the one thing that he didn't mention because he's, he's shy, is that we learned so much about how to design the Phase II, that it really allowed us to make this small, de-risked Phase II program that's currently enrolling patients, that we're quite confident is going to, as we like to say in the company, ring the bell and show the cognitive benefits of treating patients who have Alzheimer's disease from neuroinflammation. Terrific. Yeah, a lot of great points there. Maybe one area we could dive into a little bit more that is kind of beyond some of the inflammation markers and proteomics. We also saw MRI imaging come out later on. Can you tell us more about what you learned from the imaging and how to interpret it? Yeah. So I'm glad you asked about that, Joel. That was the nice segue into what I wanted to discuss next. So one of the really... You know, when I think about Alzheimer's disease, we talk a lot about amyloid, we talk about tau, and we even talk about neuroinflammation, but that's not really the disease. The disease is loss of cells. It's neurodegeneration. So your ability to show a change in amyloid or tau or neuroinflammation is only important if it changes the brain in a way that allows you to repair or recover symptoms. So one of the things that we did in that Phase I study was we were testing out some newer technology that allowed us to look at microstructural changes. So the field's pretty used to what we call volumetric changes, so they're looking at how the brain volume changes over time in Alzheimer's patients. That's a really crude way of looking at it, and it takes a really long time to see changes in brain volume. 12 months minimum, depending on where they are in the disease, and even longer when you're earlier in the disease because small things are changing. It turns out that MRI, especially diffusion imaging, can capture a lot of information that's been used in the research setting, but hasn't really been used in clinical research and certainly in clinical practice, that allow us to look at microstructural changes. So one way to think about this is, if you're looking at brain volume changes, it's kind of like sitting at the space station looking at Earth from space, right? Or even at the United States. To see changes in the volume of the United States would take a lot. But what you could do is you could zoom down to the level of Google Maps, and you can see that cities are being built or they're being broken down, right? You can have that extra level of detail. So there are things, there are microstructural techniques using imaging that allow us to do that. And one of the things that we're looking at, as RJ alluded to, is something we call white matter metrics. Now, white matter is just a fancy name for the axons, the fatty coating around them, called myelin, and the water around that. It turns out, when you have degeneration, typical degeneration, the first thing that goes is the connections between two neurons. Those things go away. The second thing that goes is those axons that connect one neuron to another, goes away. Then finally, the cells die. The beauty of white matter is that it can repair itself. So if you have a neuron that's still alive, you can actually repair and introduce new axons and form new connections. Once the cell dies, it's a whole different story. We don't. That's a resurrection story. We don't have those types of therapies. But the beauty of these MRI metrics is it allows you to see these microstructural changes over time. We weren't entirely sure how long it was gonna take and what we would see, but we know that the drug, at least in preclinical models, has a very profound effect on white matter. In fact, if you look at some of our publications in the multiple sclerosis space, you'll see that the drug has this amazing propensity to remyelinate and reintroduce axons. And so now we have a tool to measure that. And what we were able to show over a 3-month and then a 12-month period of time in patients that went into an open label extension, is an increase in these white... or an improvement in these white matter metrics, to the extent that the company that we worked with, Imeka, who does this full time, their CSO said they've never seen changes like this following a treatment. So these are techniques that are novel, they're unique, but they allow us to look at structural changes, so downstream of amyloid, downstream of tau, downstream of neuroinflammation, that actually correlate much better with clinical progression than the more volumetric MRI changes. So we're extremely excited about that. We're using that in our Phase II study. And we think this is gonna be a way for us, as R.J. mentioned, you know, we talk about de-risking, so we do trials more like oncology. We enrich patients. We're using highly specific metrics that are relevant to the drug and also relevant to the patients. Yeah, so let's segue to the phase II trial design, because as, as CJ said, as I said earlier, we learned a lot from the phase I, and CJ just reinforced that we're using novel metrics. But the MRI imaging is not the only novel metrics we're using. And so maybe, CJ, you can give a brief overview of the design, a brief description of what the, you know, what is unique about it, and why it can be fast, why it can be small, and why you are quite confident that with using a really fit-for-purpose endpoint, that you're gonna give XPro the opportunity to shine in these patients. Yeah. Thanks, R.J. So, as I mentioned, I think it makes sense to just give a little overview of how we approach clinical development. It will make sense with this sort of conceptual framework. So number one, I mentioned this before, we believe that the mechanism of our drug should match the patient's biology. Again, if we have an anti-inflammatory, the patient should have inflammation. This enrichment strategy is how oncology works, and as you're probably aware, oncology has, you know, the most successful drug development program, at least especially considering compared to neuroscience. We believe you need to use metrics that are relevant to the expected benefit of the drug, but that are also relevant to the disease, and I'll talk about that a little bit more in a minute. We also believe you need to be progressive in trial design and outcomes. This is sort of a necessity for small biotech because we don't have the luxury of doing, you know, 4,000 patients over 5 years, you know, $250 million studies. It just doesn't work. But it has to anchor to something that the field understands. And then finally, I think, you know, we, we err on the side for what's best for the patient. So in other words, you know, if we're making a decision, all things considered, you know, a 6-month study versus an 18-month study, you know, the burden to the patient in an 18-month study is quite high. And there's other reasons for that as well. So that's sort of the framework on which we sort of, you know, proceed forward. So the trial itself, let me just start with that, is. It's a 6-month study. It's 2-to-1 randomization, so drug to placebo, so patients are more likely to get on drug than placebo. And we're using, as our primary endpoint, a clinical assessment that was designed specifically to capture cognitive changes that occur in the patients we're examining, which is early AD patients. Early AD consists of MCI patients and mild AD patients. So this is... I'll talk a little bit more about the EMACC in a second. The study, however, was powered on our key secondary endpoint, the CDR. The CDR is an assessment that is an approvable endpoint, and that's important for obvious reasons. Again, we're using some of these novel biomarkers, so we're using the MRI microstructural imaging. We'll be looking at blood. But we also have a couple other assessments that we're using that are maybe unique. One of them is something called the Goal Attainment Scale, and what I like about this specific assessment is, if you think about a trial that has 201 patients, which is what ours does, you essentially have 201 patients that have different types of Alzheimer's disease. The Goal Attainment Scale basically allows you to capture clinical and cognitive changes that are relevant to that patient. So let me just give you a brief example. If you have two patients come in, they have Alzheimer's disease. One patient may come in and they say: "You know, you know, I just wanna play pickleball three times a week. I love playing pickleball. It's something that I can't do with my dementia. It just doesn't really work." You may have another person that comes and says: "I you know, I just wanna be able to walk my dog around the block. That's it." Now, with normal, typical assessments, you may not capture that, right? This person may be playing pickleball 3 times a week, and this other person may be walking their dog, but that doesn't necessarily show up on the assessments. This allows you to actually set and manage goals that are specific to the patients and gives you the flexibility to really understand how well the drug works. So that's one of the unique aspects of the trial. The other thing that we're using is something to control for placebo effect. Now, what's interesting about the placebo effect is most people don't typically think of the placebo effect in Alzheimer's disease. But if you look at the way that Alzheimer's is assessed, typically, the CDR Sum of Boxes or the ADAS-Cog, which is not a part of our program, but those are the two common ones, those are interviews with caregivers. So the expectations of the caregivers really weigh into their responding, and we're working with a company that has identified really a personality trait, for lack of a better description, that can identify people that may be more likely to have a placebo effect. And not to get all nerdy in the statistics, but it can account for a fair amount of variance, up to about 35%. And to put that in context, you know, if you can account for 35% of all variance, it really makes a difference in whether or not you have a significant trial or not. So those are the two key things. Those are the key elements of the study. The real question is: why can we do a six-month study, and why are we using EMACC? So it's actually quite simple. Patients that have biomarkers of inflammation, they actually progress faster in the disease, and the variance between patients and progression is reduced. Mathematically speaking, that gives you an enormous power to do shorter trials with fewer number of patients. So that's the first thing. The EMACC, again, is purpose-built for, to capture changes that occur in early AD. And why is that important? Well, if you look at what's typically used, the ADAS-Cog or the CDR, what happens is, in early AD patients, you get no change, no change, no change, and then it drops off the map at about 12 months. So... This is your placebo control group. So you need a longer trial just so you can see a difference between your therapy and another therapy. So using those metrics, novel metrics, being able to select patients that are gonna progress faster, gives us an enormous ability to see changes early and quickly. Yeah, and I would wanna emphasize that, based on the Phase I trial and all the work that Malu and her teams have done in the preclinical work, our expectation is that we're really going to be able to stabilize cognition. In other words, instead of patients continuing to get worse, but at a slower rate, which is what the current expectation of the anti-amyloid therapies are, our goal and what we hope to be able to demonstrate with the Phase II, is that once you start on XPro, cognitive decline ceases. And we believe that that is related to everything that CJ said, and maybe I can even have Malu comment on this concept of, you know, treating, you know, Alzheimer's as a system. I mean, in the brain, you have neurons, oligodendrocytes, microglia, and astroglia all working together to make cognitive function normal, and Malu is spending a lot of time researching on how diseases in the periphery, diabetes, obesity, cardiovascular disease, affect that cognitive unit. One of the great advantages of XPro is it treats both the central disease of Alzheimer's, and it treats the peripheral source of chronic inflammation, which is driving the Alzheimer's disease. Anything you want to add there, Malu? Yeah, I would say that if you look at the genetics and the studies, natural history studies that we've had for many years now, on Alzheimer's and dementia, these diseases are not a neuronal problem. The neurons that are dying and degenerating are not doing it alone, and they're doing it because of neglect or, in many cases, outright toxic activities of the immune system as you age, as you have these environmental exposures. And so to really get at the crux of the problem, that is immunological dysfunction, that then increases your risk for neurodegenerative disease, you really have to think about the immune, and inflammation equation, as a target for drug development, instead of saying that it's a by-product. By targeting the soluble TNF-dependent inflammation that we know from other preclinical studies really contributes to neuronal dysfunction and eventually death, that's the novel approach here that we think will be applicable, not just to Alzheimer's and dementia, but other neurological diseases that also have chronic inflammatory components. Maybe just to elaborate on that point, we've been talking all this time about the brain. Are there any effects in the body beyond the brain that you might expect to see with XPro? Yeah. So what's interesting is this, biologic, that soluble TNF-dependent, and specific, is administered peripherally, which means that you're going to have benefits of quenching the inflammation in the peripheral circulation, in peripheral organs, like the gut and the bloodstream. And we know from a lot of epidemiological studies, that these chronic inflammatory conditions that have been mentioned, diabetes, obesity, metabolic syndrome, are risk factors for Alzheimer's and dementia. And so by taking care of the peripheral inflammation, you protect the brain, and it's because there's a communication between the periphery and the brain that's ongoing. But this communication or crosstalk breaks down as you're aging. It certainly breaks down with environmental exposures, sometimes lifestyle choices, like bad diet. And so what you have is sometimes a condition called leaky gut, that is actually present in a lot of people with neurodegenerative disease. We don't know necessarily that it's a cause of the neurodegeneration, but when you have a leaky gut that we believe a soluble TNF-dependent inhibitor will take care of, then you will have less permeability across your blood-brain barrier. And if you have a better blood-brain barrier, then you keep toxic substances outside the brain. So by treating the peripheral inflammation that compromises brain function, we think that you're going to afford a lot of benefits that are outside the brain in organs that are chronically inflamed. Great. So maybe circling back to the Phase II study, CJ, you were talking a lot about the design and the... There's lots of endpoints in the trial that we commonly see in Alzheimer's studies, like CDR. You know, though EMACC is a primary endpoint, you know, which is, as you described, purpose-built for these kind of earlier stage Alzheimer's patients. And I guess on EMACC, any sense if that could potentially be a regulatory endpoint down the road? Yeah, so great question. Right, right now, it is not an approvable endpoint. The FDA specifically has a guidance on that, with basically a checklist, and part of what we're doing in this study is validating this as an endpoint that could be used in future trials. Whether or not we'll meet it before we do a Phase III study, I don't know, but that's why we powered it on the CDR. So that we could, you know, we can sort of have our cake and eat it, too, right? If we can get the EMACC approved as a primary endpoint, and I think we have a really good chance of doing it, to be honest. The background work that our people have done to validate this is really quite an amazing... But even so, you know, we're hoping for the best, but we've planned for—we have to use CDR. So we'll- Yeah, if I can jump in there- We're in good shape either way. If I can jump in there, Joel, this is a good question. In fact, I think the regulatory agencies realize that part of the traditional endpoints of ADAS-Cog and CDR are not quite the right tools. For instance, in the Lilly trials, they're not using ADAS-Cog or CDR as the primary endpoint. So they're beginning to allow companies to validate new endpoints, and as CJ said, I mean, we are doing that with EMACC. I can't emphasize how important it is that EMACC. We'd like to use EMACC, because one of the things that EMACC does capture is patients who actually get better. All the other metrics only can tell you if you're getting worse, and as I mentioned earlier, in the Phase I, we had two patients that got better, and we wanna be able to capture that data, because wouldn't that be a great thing to have on our label? That actually, X% of patients showed improvement, because that is a unique offering in the field of Alzheimer's disease today. Yeah, I wanted to add something that I actually forgot to mention, which is actually critically important. The EMACC is an objective assessment. The CDR and the ADAS-Cog are not. They require somebody's interpretation of how the patient is doing, as opposed to the EMACC, where we're actually objectively assessing their cognitive ability. And because we're looking at change over time, we get a very accurate snapshot of that. The other thing that I wanna mention is, we actually do more routine measurements with the EMACC than you can do with something like the ADAS-Cog or the CDR. And the reason that's important is because there's a lot of noise in response in clinical trials. One way to get around that is to do more routine measurements, but you have to have an assessment that allows you to do that, and it just so happens that the EMACC allows you. So not only is it fit for purpose, but it's objective, and we can measure it more routinely to reduce the noise, which all benefit and de-risk the program significantly. Great. So what's the status of the Phase II trial? You know, how is enrollment going, and, and when can we expect data? Yeah. So, as you know, we've actually been putting out press releases, so most people know this, but we are currently. The trial is open in, I believe, 9 countries. We're both in North America, Australia, and U.K., and Europe. The enrollment is going well. The expectation is that we should complete enrollment by mid-year. Six months or so after that, we should have top-line data, and then the next important milestone for us will be actually our end of Phase II meetings with the regulatory agencies, like the FDA, MHRA, and EMA, to help to get their buy-in to our Phase III design. Our expectation is the Phase III design will look very similar to the Phase II. I think that CJ and his team have done a very careful job of designing that Phase II to really look like a registration trial. But at the end of the day, we need to see the results, which we hope to have by the end of the year, and we need to actually then, you know, dig into the data and come up with the perfect design. Because at the end of the day, you know, we understand that what investors and potential partners are looking for is a drug that safely treats patients with Alzheimer's disease and ideally stops their cognitive decline, and we think XPro is that drug. Great. A couple of weeks ago, INmune Bio announced that the clinical hold was lifted by FDA, and congratulations on achieving that. Tell us a little bit about what went into the lifting of the clinical hold, and any- Uh- ... implications and what? Yeah. Thank you, Joel. This has been. This was a tremendously frustrating problem, and I think the best way to describe it is that in drug development, you know, you have Phase I, Phase II, Phase III. ... drug manufacturing and validation and testing procedures are understood to be less mature in Phase I, more mature in Phase II, and by the time you get to Phase III, you've got to be really ready for commercialization. That is the expectation across all regulatory agencies. For some reason, we believe the FDA was holding us to really kind of a Phase III standard for a Phase II trial. All the other regulatory agencies, which allowed us to keep the trial to open and keep the trial going, really treated us on a Phase II standard for some manufacturing issues. Had nothing to do with safety, had nothing to do with toxicity, had nothing to do with anything other than some, I would say, quite arcane manufacturing issues that were unique to the FDA. So that's behind us, thank goodness. Lord knows, it was a tremendously frustrating time for the company. When it started, I had a full head of hair, and now I'm bald. But, I mean, it was really quite quite a difficult time, and now we are really anxious to tell investors, particularly institutional investors, more about the company, more about our trial, more of why XPro is the right drug to treat neuroinflammation. And as Malu said, neuroinflammation is kind of the original sin. It is what really promotes neurodegeneration, the formation of plaques and tangles, and we believe that by targeting the original sin, we'll make a real difference in patients' lives. Great. And with the lifting of the clinical hold, are there any plans to kind of take that option to enroll patients in the U.S. in the Phase II study? Yeah, thanks. We could, but, you know, what happened is that as we worked very hard while we were on hold to open up all these other sites in Europe and Canada, by the time we would get a site open in the U.S., we will have completed enrollment in the Phase II trial. So the U.S. will be a very big part, probably the biggest part of the Phase III program, but we do not have any expectation that we'll be enrolling patients in the U.S. in Phase II. Now, just to be clear, all of the countries that are participating in the AD02 trial are, you know, they're, quote, "first-world medical regulatory environments." These are all countries where the data can be used across you name it, whether it be the U.S., Canada, Australia, U.K., or any of the... or the EMA or even Japan. These are all first-rate countries. We are not working anywhere where there's any question about the quality of the clinical trial, data we'll be getting. Okay, great. I know we're getting close to our time, but there's one more question I wanted to throw out there before we close, and it's, you know, any opportunities in neurology beyond Alzheimer's disease for XPro, and any diseases that kind of stand out to you as good opportunities, especially if we see the Phase II trial be successful? Malu, who is a named professor in a Parkinson’s disease institute, will answer this question, so... That's an excellent question, Joel, and I see incredible opportunities for this particular target because inflammation is the hallmark of all neurodegenerative diseases, Parkinson's, ALS, frontotemporal dementia, and in fact, other neurological diseases like depression. And it's important to recognize that in the field of neurodegenerative disease, we often can learn from one trial and design the next trial in a different indication. And I'm very excited that, based on the preclinical work that my group and others have done, this is going to be a really good opportunity for Parkinson's, where we know that the dopamine-producing neurons are very sensitive to TNF, very sensitive to inflammation. Those, in fact, were the first studies that we did back in 2002. And it was very clear that if you could block the soluble TNF signal, like, you know, XPro will do, you can rescue the dopamine-producing neurons and prevent that loss at 70%. That would give you a clinical diagnosis of Parkinson's in motor disturbances if you were a patient. So I'm really excited that it's going to be a huge opportunity for a lot of different neurological diseases, in particular, those that I really started in. Yeah, and as CJ said, those 82 publications, they're probably at least 12, maybe more, neurologic diseases that we have all the preclinical data we need to jump into the clinic, right? Really, Alzheimer's disease is the start of really a whole neuro franchise. And one of the beauties of all the biomarkers that CJ is using is many of these can be applied across different diseases. So everything we're learning in Alzheimer's disease, we're gonna be able to apply across these other diseases. We often get asked how we started in Alzheimer's, and I will say that it was because CJ and his team actually applied for a grant to the Alzheimer's Association, and they really provided a very large Part the Cloud award to the company, which really kind of caused us to step into the Alzheimer's space as our first entry into neurodegenerative diseases. Well, I'm gonna give Malu a little credit for that. You know, for years, we've been told that inflammation's not a thing in neurodegenerative disease, and Malu said, "No, no, no, it's time. Write the grant, write the grant." I will say, I was reluctant to do so, but Malu was adamant, and to her credit, you know, Malu's, she's my mentor, so I'm reluctant to say this all the time, but Malu is almost always right, so... Terrific. Thank you so much for that great kind of overview of everything today. And I think that's a great place to close. I'll turn it over to Mike. Yeah, great. Thanks, Joel. Thank you to RJ, CJ, and Dr. Tansey for the great overview here today. Appreciate all the participants joining us. If you're interested in connecting with the company, please reach out to your Baird representative. We'd be happy to connect you. But thanks again to everyone, and hope you all have a great rest of your Tuesday.