INmune Bio Inc. (INMB) Earnings Call Transcript & Summary

Okay, everybody. Thank you very much for joining us, and welcome to INmune Bio's webinar on Phase Ib data on improvements in multiple biomarkers of white matter pathology, including a reduction of pTau and Alzheimer's disease. I'm David Moss, CFO of INmune Bio, and we are excited to have a distinguished group of panelists today to share with you our expanded data on our recently completed Phase Ib trial with XPro in patients with Alzheimer's disease. This event is being recorded and will be made available on the company's YouTube channel, which can be found on the company's website a few hours after the close of this discussion. We expect today's webinar will last about an hour, with 45 minutes of time allotted to the panel and the rest for Q&A. [Operator Instructions] I already see that there's a few there. Before we begin, I remind everyone that except for statements of historical facts, the statements made by management and responses to questions on this webinar are forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties that can be -- that can cause actual results to differ materially from those in such forward-looking statements. Please see the forward-looking statements disclaimer on the company's earnings press release as well as risk factors in the company's SEC filings, including our most recent quarterly filing filed with the SEC. There's no assurance of any specific outcome. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made as the facts and circumstances underlying these forward-looking statements may change. Except as required by law, INmune Bio disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances. We're very excited to share with you the data from our completed Phase Ib trial. And without further ado, I'd like to pass this webinar over to RJ Tesi, CEO. RJ?

Thank you, David. Good afternoon and thank you for joining. This is INmune Bio's third webinar presenting findings from the Phase I trial in patients with Alzheimer's disease. I remind you, this is an open-label biomarker-directed dose escalation trial in patients with Alzheimer's disease who have neuroinflammation. The trial had 4 goals. We have successfully reached all of those goals. The first goal is to demonstrate safety of XPro in the target patient population. Patients with Alzheimer's disease are elderly with many comorbidities, including cardiovascular disease, diabetes, obesity and other lifestyle diseases of the modern era. Safety is a key first hurdle. XPro is safe. And in this patient population, it is a good choice for the patient group. The second goal was to demonstrate target engagement. That is does XPro decrease neuroinflammation with patients with Alzheimer's disease? The answer is unequivocally yes. The third goal was to demonstrate downstream effects of target engagement. Using an expansive and novel biomarker package, we have shown that when XPro decreases neuroinflammation, it decreases neurodegeneration, improves synaptic function and improves apparent fiber density. Today, you will learn that it promotes remyelination. Three elements of our biomarker package focus on white matter quality. Some have wondered why INmune Bio has focused on white matter in patients with Alzheimer's disease. INmune Bio believes that in Alzheimer's disease, white matter matters. That is white matter pathology occurs early, can be quantified, and XPro can repair the pathology. The importance of white matter pathology, along with the focus of therapeutic intervention in MS, has been ignored in other CNS diseases where it occurs, and it occurs in many. It will be ignored no longer. The final, and arguably, the most important purpose of the Phase I study was to provide the 3 Ds for the Phase II study: dose, duration and design. In this, the Phase I study has been a spectacular success. Because we understand exactly how XPro works in the brain of patients with neuroinflammation, we are confident that a 200-patient 6-month blinded, placebo-controlled trial will allow us to answer the most important question that we are all asking. If you get rid of neuroinflammation in patients with AD, Alzheimer's disease, for long enough, does it have a positive impact on cognition? We will not be presenting any cognition data beyond the anecdotes we have previously provided. We believe cognitive changes are not interpretable in a 12-week open-label study in small numbers of patients at various stages of disease. We look forward to addressing this question with the adequately powered blinded, randomized, placebo-controlled Phase II study that we have planned and you have heard about. CJ?

Thanks, RJ, and thanks, everybody, for joining. We are pretty excited to have you on the line here. My part in this is going to be pretty short. And we've had the privilege to have Max Descoteaux from Imeka to talk a little bit more about the imaging, which we think is really, really exciting. But first, let me remind you what the trial design was. As RJ mentioned, this was a Phase Ib study. And as you're aware, Phase I studies are really about demonstrating safety and trying to find the optimal dose. As RJ mentioned, we used a variety of different biomarkers. And we have presented that a number of different times over the last 2 webinars. And so I won't be rehashing the data that we have with -- except for a few mentions here and there. But the study was 3 months in duration, and what I'm going to be presenting is really a change in 12 weeks. There's some imaging data Max will talk about that goes out a little bit longer, but the CSF and the proteomic data that I'm going to be talking about is really what happens within 12 weeks. So just to remind you, the patients in our study had to have a diagnosis of AD, and they had to have one of our biomarkers of inflammation. What's unique to this study is that the patients could have any stage of disease, and that I'll talk about in just a moment. Again, the study goal is to demonstrate safety and show that we can reduce biomarkers of inflammation, neurodegeneration so that we can identify the appropriate dose moving forward. As David mentioned, we have completed the 12 -- the Phase Ib study. And what you're seeing here are the number of patients that have completed 1 of 3 doses. So patients were either treated with 0.3, 0.6 or 1 mg per kg. Most of these patients were female, about 2:1, which is about what you see in Alzheimer's trials, maybe a little bit more. And the average age is about 70 years. As you can see at the bottom here, the range of disease severity is quite high, which makes anything other than looking at biology a little challenging. And I would argue even then it makes it challenging because the biology changes as the disease state changes. And so some of these biomarkers that we're going to be looking at that have shown consistency across different disease stages is, in some regards, quite remarkable. So I'll remind you that the way that we assess biomarkers is not through one specific matrix. We want to be able to make sure that what we're seeing is reliable across multiple matrices and different platforms. And so we've really relied heavily on the MRI and the proteomics data provided by Proteome Sciences, and I will talk a little bit about that. I have Dr. Ian Pike on the line as well that will be able to address any technical questions that you may have regarding this data in the Q&A session. So why do we care about white matter? RJ mentioned it a little bit, but here's our hypothesis of neurodegeneration. What you have here are 2 neurons, and these neurons are connected to each other at the synapse here. The synapse is where these connections occur. And when Alzheimer's or any neurodegenerative disease starts, the first thing you lose is the connections between neurons. Subsequently, you lose remyelinated axons. And then ultimately, you lose the neuron itself. And of course, our position is that neuroinflammation is what drives the loss of synapse and the white matter. The reason we care most about this is where we feel you can repair and rebuild. Once the cell bodies are gone, we think that is too late. That ship has sailed. So we are focused on white matter, measuring white matter to determine and convince ourselves that we have a product that could potentially make a difference in the clinic. And I want to share that with you, the new data we have today. I want to start -- although I said I wasn't going to talk much about neuroinflammation, I do want to show one specific slide here. So this is our CSF inflammatory composite across multiple different doses. And I think the thing that I want to point out is when we -- when we're looking for the dose to move forward, we see this 0.6 dose gives us a nice dose response, which suggests we have -- it got exactly what we needed as it relates to identifying the right dose. This CSF inflammatory composite is representative of these cytokines and the target, Olink cytokine panel. This is cerebrospinal fluid. And these 37 analytes are the ones that were within the limit of detection of the assay. So what you're seeing is a composite of all patients at different doses for each of these analytes. Next, I want to talk a little bit about the synapse. So we just received proteomics data not so long ago, and there's a massive amount of data. For those of you that have looked at proteomic reports, there's just so much to go through. So what we want to do is give the high-level top line results that we think are really important as it relates to our white matter story and just know that at the final report, we will have more extensive data that mines this even further. So why do we care about the synapse? And what do we see? It turns out that the synapse is extremely complicated. Here, you can see on this right-hand side what we're calling this presynaptic neurons. So information passes from this presynaptic neuron to the postsynaptic neuron. And as you can imagine, it's extremely complex. There's a lot of things going on, including neurochemistry, energy regulation, release and recapture of some of these transmitter systems. And you can imagine that having an effect, the synapse would require changes in multiple different levels. And what we're seeing here in the proteomics data is that XPro improves biological processes involved in the majority of synaptic formation and function. And these are just sort -- the most obvious changes around. And so as we think about how our drug might be working, we want to make sure that we are looking broadly across the pre- and postsynaptic neuron and all the different functional changes that we see. So this is just added evidence that the therapy is doing what we expected to do, at least as it relates to what we've learned in the animal models. So the final thing I want to talk about before I pass it over to Max is white matter. And this is the data that many of you have seen when we released the data where we're looking at changes in Phospho-Tau. So what we're looking here is changes -- log ratio changes from baseline to week 12 in Phospho-Tau 217 and 181. Then you can see 217 is superior to 181 as it relates to treatment response. And so why do we care about that? So what I think is not as appreciated as it should be, is that tau is a measure of white matter pathology. And what you can see here in these little marks, a tau stabilizes these microtudial proteins and keeps the axon in formation. And once it becomes phosphorylated, these microtubules become destabilized and begin to disintegrate. Phosphorylation also increases neurofibrillary tangles, which are the pathological hallmark of Alzheimer's disease. As it relates to phosphorylated Tau, there are many different species, but I think the most recent evidence suggests that the phosphorylated tau at 217 and 181 [indiscernible] to changes over time, and I think our data support that. So let me just show you another -- one more and final slide as to how [indiscernible]. And what I'm showing you here is, to simplify things, are patients treated with the low dose and high dose. And what you can see is a very large reduction with very little variability in patients treated with 1 mg per kg of XPro over the course of 12 weeks, whereas patients treated with a low dose, we do not see those changes. And so these collectively suggest at least, as it relates to the proteomics, that what we expect to see with the white matter, we are seeing. And now I'm going to turn it over to Max so he can share the remaining imaging data. Max?

Thanks, CJ, and thanks for this great opportunity to present results and also the technology that leads to this quantitative measurements of white matter. And so the goal for the next 15 minutes is really to educate about white matter, how we can quantitatively image it non-invasively and show you the latest results from the Phase Ib trial of INmune Bio. And so why, in the first place, study white matter in Alzheimer's disease? Well, it's been very well known here. If you see a healthy control brain on the left with gray matter and white matter, it's very well known that with aging and with Alzheimer's disease, you lose gray matter, so gray matter atrophy, especially so in the ipocempus area, this is the memory center of the brain. But what's less known at that also white matter, what you see here in dark black is also atrophied with Alzheimer's disease. And as you zoom into the microstructure of white matter, well, lots of evidence that have been published in years of research about losing axons, demyelination and a lot of macrostructural abnormalities with Alzheimer's disease. And so the holy grail here is try to have noninvasive markers of white matter that are sensitive to these phenomenons. And I really like these little drawings here, and you try to keep those in mind for the whole course of the talk. Here, axons are in green. These are the little tubular connections that connect different neurons. They are surrounded by myelin in purple. This is the myelin sheet that allows electrical conductance between neurons. And they all have their own microstructural environment of microglia cells, oligodendrocytes and astrocytes. And as you get neuroinflammation, it's not that the extracellular space is increased. There's just more water around axons. Microglia is activated, which eventually leads to lose -- loss of axons and loss of myelin. So everything in what you're going to see later is whatever is related to axon is going to be green. Whatever is related to myelin will be purple. And whatever is related to extracellular water will be blue. And so if we play biopsy here, so if we slice through these axons, so we take a cut through them and we put the tissue under the microscope, this is typically what you see if you're staying for myelin. But now I'm helping you by coloring this myelin synthesis under the microscope. So whatever is blue is extracellular water. Whatever is green is axons that I've sliced through them. And whatever is purple is the myelin sheet. And so the real -- the holy grail here of noninvasive imaging is to replace microscopy. It's not to have to open someone's brain to have indication of inflammation, axonal loss or demyelination. And for that, we use MRI. And it's the same old machine that you're used to see. It's just that we use a specific sequence and technology called diffusion-weighted MRI, which is sensitive to how water molecule navigates around axons, inside axons so that if there are abnormalities, demyelination or events, the way the water molecule drives around this medium will be affected and will be translated into quantitative markers in our images. So it's a little bit like us driving down the roads and being confronted with street blocks and roadblocks or flooding from incidents. And so the fusion of water molecule is sensitive to these phenomenons to water inside, outside axons. And so this is how we can create 3 markers. The first marker is our marker of inflammation. It basically quantifies the amount of blue here on these slides, how much water is there present in every brain location. So in 2D, this is called a pixel. In 3D, it's a voxel. So how much water occupies the voxel so that if you're confronted with an abnormal Alzheimer's tissue, and this is a real tissue here from a mouse model just to give you an indication, this clearly shows that there is an increase in extracellular water. So this blue compartment here, we can quantitatively extract it from the diffusion MRI and turn this into a map or a metric at every brain location. So this is our first marker. It's our marker of extracellular water, which is a proxy to neuroinflammation. Our second marker is apparent fiber density. Here, we switched the focus to the axons. Apparent fiber density is proportional to the amount of axons in the voxel. So the more green axons here, the tighter they are, the higher the apparent fiber density. So again, if you take an Alzheimer's disease tissue, you can clearly see that here, axons are distorted. Some of them are swelling. A lot of them have been lost. And so overall, in this pixel or in 3D in voxel, we lose apparent fiber density with axonal degeneration. So that's our second marker. Our third market is related to myelin. And so again, using my analogy here, if I color myelin sheets in purple and I'm confronted with a pathological tissue model here from the Alzheimer's disease, you can clearly see that the myelin sheet is granulated, is distorted. Some of it is lost. And so bottom line here is that it's easier for water molecules to traverse axons. So it leads to a tissue tensor that is fatter than a normal tissue tensor here. So if you account for free water, you account for crossing fibers of axons with apparent fiber density, the third marker, radial diffusivity is a proxy sensitive to myelin. So if I encapsulate that in the final slide, if you have healthy tissue under the microscope and pathological tissue under the microscope, what you expect to find from MRI is an increase in extracellular water, an increase in myelins -- a reduction in myelin, an increase in radial diffusivity and a decrease in apparent fiber density. And as you will see in the results section here, this is actually confirmed from Alzheimer's disease patients in the ADNI database, which is a large public Alzheimer's disease neuroimaging consortium over the course of 2 years. So I'll be showing you that data to put INmune Bio's results into perspective. The last feature about white matter that's crucial is that we have 100,000 miles of such axons packed into our head. And these axons organized themselves into bundles, into connections that serve a specific brain function. So I've highlighted a few of them here in blue, red, yellow where here is the language tracks, the motor tracts, the memory tracts, the language tracts. So you can actually group axons together at the macrostructure level and wonder what is their microstructure going on. And so in the end, we can ask them where? So where is the Alzheimer's pathology installing itself? And what I'm going to show you today, we focus on the Alzheimer's disease bundle. So it's a composite family of white matter connections that I've been taken out of 20-plus years of publication where it's been shown that mild cognitive impairment in Alzheimer's disease affect these brain locations. for the most of them that are involved in a temporal lobe where we have the memory center and some of them are implicated in the limbic system. And so all the results that I'll be showing you today are microstructure markers, so our biomarkers computed in the specific brain locations. So in the end, what you truly have here is a virtual dissection and biopsy tube that it's noninvasive. We can select the where and we can study the how. So we have our maps of free water, apparent fiber density and myelin biomarkers, and we intersect them with our Alzheimer's disease bundles. So we have the where and the how. And so how are our 3 markers and where are these specific brain locations. So if we were to study a different disease, MS, or different neurodegenerative disease, we could select different brain locations that are specific to the pathology. So now let me summarize the final results of the INmune Bio Phase Ib trial. CJ already covered the demographics of the study. I'm going to be strictly focusing on the 1 mg per kg dose, which was the highest dose. So first, let me walk you through these results. As a reference, you will always have this dark gray curve that illustrates the ADNI database with 36 Alzheimer's disease patients over 2 years. So we had a baseline, 3 months, 6 months, 12 months and 2 years of data over 36 Alzheimer's disease patients. And as you can see, free water tends to increase with time. And after a year, it's more or less an increase of 11% in free water. This is for the Alzheimer's disease bundles, and what you're seeing in the Y axis are a percent change compared to baseline. Now we focus on the XPro in blue here. So you see the evolution of XPro after 3 months, 6 months, 9 months, 12 months. You can see that ends here. So we start with 6 patients at baseline in 3 months, then 5 patients at 6 and 9 months and down to 3 patients after 12 months. And after 12 months, we see a reduction in free water of 46%, which is striking. So all that to say that it seems that extracellular water or free water has been reduced. We're reducing, we're filling up the space with other things than free water. First biomarker, first result. Second, apparent fiber density. Again, the reference curve is ADNI where you see a reduction of 4% to 5% after a year. So losing axon density in a normal longitudinal cohort of Alzheimer's disease patients. On XPro, our patients are improving in axon integrity, up to 17% increase after 12 months. So this also seems to be indicating that there are more axons. Axons are probably more cylindrical, more tonic indication of most likely a tissue repair here. Last but not least is radial diffusivity where this is our marker of remyelination. Again, in Alzheimer's disease, you see an increase in radial diffusivity, which means a decrease in myelin content, a slight increase, that's true. But with XPro, again, a trend, a real decrease in radial diffusivity, which seems to indicate that there are more obstacles and maybe some myelin restoration and rescued in the process. Finally, we also looked at total white matter volume. So this is at the macro scale. So we're not talking about the AD, Alzheimer's disease bundle here. We're truly just focusing in general in the white matter and what we see across the 12 months, although this is variable and the ends are quite small, where we would expect a decrease of white matter volume just like decrease of gray matter volume, we actually see some sort of stabilization or a slight increase in total white matter volume. And if we focus on the famous temporal lobe where the hippocampus stands, we also see a stabilization or a slight increase in left temporal lobe volume. All of what I said today is with really small ends. Proper statistics have to be taken into account. And like RJ said at the beginning, this will be done in the Phase II trial with proper power. So in conclusion, I hope I've convinced you that white matter matters, that it's a key component of the Alzheimer's disease pathology, that neuroinflammation, axonal loss and myelin disruption is happening as we saw in the ADNI database, that we can quantify it noninvasively with our virtual dissection and biopsy tool to know where the white matter is disrupted and how it can be rescued, if at all. And I've just shown you that XPro reduces free water, increases apparent fiber density and improves myelin over the course of 12 months. And this -- I didn't show you the plots in the interest of time, but if we do correlate CSF inflammatory marker and pTau markers with our apparent fiber density marker or our marker of free water, the correlation is [ done ]. And I think you've seen the free water correlation in a previous webinar. So with that, I'll pass it on back to CJ, and I'd be happy to answer any questions you have in the chat or live afterwards. RJ, I'll pass to you.

Yes. Thank you. Max, thank you. Max, thank you very much. I think there's a couple of important things that I want to reinforce about Max's talk. You're probably a little surprised we gave him so much time. But what we have found, what David and CJ and I have found as we've talked to investors, no matter how sophisticated a neuroscience as they are, all these concepts that we're bringing as far as these MRI analytics and our focus on white matter have been new to them. And as you know, when something is new, it can be confusing, particularly because in the CNS, there's a lot of complicated science. Max has a remarkable ability to really communicate what he's been spending decades developing with his technology, looking at white matter, his virtual biopsy. So one of the things we really wanted to bring to you was that what he was looking at. Because if you don't understand that, then you can't really understand those 3 remarkable slides he showed you at the very end where over 12 months, and mind you, this is a 12-month follow-up on some of these patients who have had 1 milligram per kilogram dosing every week for those 12 months, they showed continued progressive, shall we say, improvements in their white matter free water, i.e., their neuroinflammation in their apparent fiber density by their axonal quality and today, the remyelination. And I'll remind you that remyelination is not often talked about with Alzheimer's disease, but Max made the point early on that it is a very important part of the disease process. So with the virtual biopsy that we can do in a very short period of time, it takes about 5 or 8 minutes of extra scan time, we then turn that data over to Imeka. We get this treasure trove of information that really shows that XPro therapy, as I said early on, when you get -- stop neuroinflammation, a lot of good things happen. And the Phase II trial will help us determine that when all those good things happen in the white matter if you actually make a difference in cognition. So I'll stop with my comments. And David, I'll let you poll for questions there.

So if at this time, you have any questions, I'll encourage you to write them in chat. CJ, I know we had a couple of questions about the end on the patients, the 1 mg per kg. I think it's worthwhile where we started at 5, 1 to 6 and then down to 3 at the 12-month period. I think you should have probably just explain the simple reason why that happened. It's an easy reason to explain, so...

Yes, yes. Unfortunately, there -- the patients -- we didn't lose the patients. The data, the MRI collection, and Max can probably speak to this, was a little too messy. It turns out that one of the sites did a software update and didn't do the appropriate control. So we lost the quality of that data.

Yes. And another question that we get this often, and I think it's a good one to answer right now. It says people are obviously questioning why are we doing a 6-month trial. They're saying 6 months seems too short. Why not 12 months? I know, RJ, this is a softball question for you, so I'm going to toss it your way.

Yes. Thanks. So really, I want to emphasize that it's -- we are doing a trial that's long enough for us to show what we think will allow us to show an improvement in cognition. And we learned that from the Phase I trial. When you look at the changes that occur, they are dramatic in the first 6 months. They begin to slow down between 6 and 9 and then 9 and 12 months. The bottom line is we think that 6 months will be long enough. And we believe that because we are able to enrich for patients with neuroinflammation, to answer another question about those biomarkers, about 50% of the patients that were screened for the Phase I actually could be accepted in the trial. So put another way, that meant there was a 50% screen failure rate. But in focusing on those patients that have the biomarkers that we're looking for, everyone had neuroinflammation. We showed that -- we haven't shown the exact figure, but we know that from white matter free water scans that the team at Imeka did. And so we -- and patients with neuroinflammation, they progress more rapidly. So it allows us to -- with low variability and a high degree of confidence, understand that we're going to get the kind of answers we need in 6 months. I'll remind you, a 6-month trial, although it still takes 12 -- probably 18 months to enroll at best in this competitive environment, you could imagine if you're doing an 18-month trial, like if you're an anti-tau or an anti-amyloid drug, it takes 3 years to enroll that kind of trial. I mean being able to have a 6-month end point will really should, we'll see what happens when we start the trial, should allow us to enroll with some efficiency.

So -- great. Thanks, RJ. And Max, I got a number of questions here from Mayank. Thank you, Mayank. And Max, this is one right up our ally. I'm going to start with his last question first. How might be looking to validate the imaging virtual biopsies that you -- biomarkers that you use? Often we get the question is, are these validated, et cetera, et cetera. And he kind of wants to know what's the regulators' perspective on this?

Yes. There are numerous ways to validate this technology. And this has been done over the past years, to be honest, with small animal models, simulations. What I love about what we've done here with CJ and INmune and the team is get markers from totally different technologies. So CSF markers, invasive markers, proteomics. And they all -- they're not validation per se, but they're very strong evaluation in the right directions. And so I think regulators right now are looking for more and more quantitative imaging markers. We have special grants now really focused on finding primary end points that are based on quantitative and not subjective markers, and imaging is a potential such quantitative marker. And I think having a very strong reference such as leveraging the ADNI database is really strong arguments for regulators that were on -- were going in the right direction.

Great. Thank you, Max. And kind of as a follow-up, kind of on a high level, could you comment really on how you might be seeing different white matter biomarkers change with disease severity?

Yes. That's a great question, and it really also depends on the disease. So I can tell you that, for instance, when we look at an MCI group, mild cognitive impairment group, not the same brain locations are involved. So some brain location deteriorate first. So for instance, if you've really focused on the fornix and the connections of the hippocampus or the posterior singulum, which are part of the parahippocampus, these seem to be really the first location degenerating with the appearance of the pathology. And there's this retro genesis approach that suggests that the latest myelinated axons are the first to go. And so -- and it turns out that the temporal lobe and connections of the temporal lobe are the latest myelinated axons. And they seem to be the most severely affected right off the bat with MCI groups. And then the disease seems to spread towards the frontal lobe and the parietal lobe. So having a way to dissect the brain and quantify it is really the way to go to study the where and the how. And everything I just said is different for other pathologies like Parkinson's disease or MS or a traumatic brain injury. So we're going to have to adjust our tool depending on the disease.

Yes. And then just a quick follow-up at, Max, if you don't mind, before I ask a question to RJ, post one to RJ that someone asked about the ADNI data that you use as a comparator to mild to moderate AD or how do you compare the -- how did you contrast the ADNI to the level of the Phase Ib trial XPro patients?

So because of the low end in the Phase Ib trial, we haven't tried to match anything. We basically took every Alzheimer's disease patients we could. So when you see these N=36, these are the only 36 patients that we have that have all time points and survive quality control, which, when you think about it, it is rare because you have 2,000-plus images in ADNI. But to have the right patients across time for that period of time is pretty rare. So N=36 is quite high. But we have plots that we could share in the future, CJ, right? Maybe you want to comment on those, where we see how baseline values of inflammation are distributed across ADNI, and we have the INmune data on top of that. And it really confirms that the way INmune recruited patients really is clearly that the INmune Phase Ib trial patients are a lot more inflamed than the baseline Alzheimer's disease patients in ADNI. I hope that answers the question.

Yes. RJ, you had something specific in mind, I think.

Yes. Some -- one of the questions on the -- in the chat room is about whether there is any -- how the FDA will handle a positive Phase II because, i.e., there's -- we're using biomarkers. It's a modest-sized trial, 200 patients. Remember, this is a 2:1 randomization. So 166 are getting drug compared to the placebo group. I mean I think it would be almost impossible for that to be a registration trial, not because of efficacy. I am -- we're optimistic that efficacy will be quite strong. But the FDA has another requirement that they want a safety database that is adequate for them to be able to really inform the patient and clinical community about the risks with the drug. And in Alzheimer's disease, 200 would be considered low. When you look at the biogen activity, it's quite high. Most people think you probably need about 600 to 800 patients as a minimum to actually get approval, even a conditional approval for a disease like Alzheimer's. I may be wrong. As you know, in oncology trials, there are patients who -- or programs and drugs that get approval with smaller ends, but I don't see us getting that here. So I would expect that we would have to do a Phase III, but that goes back to my comment about a 6-month trial versus an 18-month trial. I mean I like an 18-month trial for a lot of reasons. And part of it is we can get through Phase II and Phase III faster than someone who's doing an 18-month trial Phase II. So thank you, David. Yes.

No, that's great. That's great. We often answered that question as well. It's a good one. CJ, to you. You believe 6 months is sufficient to show your intended results. Do you have any data to the time required before you can judge an increase in cognition by these patients?

Yes. Thanks, David. So good question. I think one of the things you have to remember is that when you look at your primary end point, there's 2 things to keep in mind. Number one is how the placebo group changes over time and what you expect will happen with your therapy. And so the reason we can do 6 months is really, more than anything, based on going into these large databases and looking at the rate of decline, the normal rate of decline in patients that have the biomarkers of inflammation. And what is very clear is that the patients that have the most inflammation have faster decline. And I think even more importantly, the variance that decline is reduced significantly. I mean I believe it's almost 2 standard deviations lower than what you get in normal population. So that really allows us to do shorter trials with smaller number of patients. So we are absolutely confident that we designed the study as rigorously as possible, and the biomarkers that we use really do give us an advantage in that regard.

Great. Thanks, CJ. I'm going to lump 2 questions together here, and I'm going to throw it out. This is probably for you, CJ or Max or both together. For pTau 217 and 181, there's data that shows the correlation between pTau levels of normalization and cognitive improvements in AD patients. In other words, does pTau have a correlation with cognition? Question number one. And the second question, although a little bit different, someone's asking, are we aware of any other clinical trials that show evidence of remyelination in Alzheimer's patients?

So yes, let me take the pTau question, and I'll let Max comment on remyelination. So there is -- 217 is pretty new, and there is an emerging literature, but it appears to correlate with clinical decline a little bit better than some of these other biomarkers, but I would say stay tuned. If you look at our data, it's -- I mean the variance is really small. I mean one of the interesting things about the literature, 217, is that it's really specific and it's really sensitive. And if you look at the response in our patients, it's -- we basically see the same thing. So I think there's something really interesting about that biomarker, and it could potentially be a biomarker of treatment response. I don't think there's any question that, that could be the case, but we'll have to show that in the Phase II study. Max, remyelination in Alzheimer's?

There are, to my knowledge, not that many papers out there. A few abstracts here and there. Just so you know, myelin -- MRI myelin imaging is harder than free water and apparent fiber density. So I have a feeling this will be coming out more and more in the coming years. And the ADNI database doesn't have a specific myelin contrast. So in a sense, we're a bit ahead of the curve here, and it should be coming -- because, clearly, from animal models and a lot of histological work, this demyelination is happening. This granulation of the myelin sheet, this deterioration of axons and myelin has been clearly shown. So I think it's just a matter of time before advanced imaging confirms the high-impact papers.

Let me put -- yes. Let me put the myelin story in perspective. One of the ways I measure how important the topic is, too, as I go on to PubMed, and I look at the number of publications. And if you look over the last 30 years, there have been like 40,000 publications on Alzheimer's disease and amyloid. There's about 12,000 or 13,000 on tau and Alzheimer's disease. And there's 1,300 on myelin and Alzheimer's disease. So it is clearly the little sister, the poor brother, so to speak. But I think it's partly because people just haven't looked that much. Part of it is because the way you preserve brains and things if you're going to look at them under the microscope. Having a living biopsy, which is really what Max's technology does with Imeka, you see a completely different picture. And I predict, I mentioned this in my lead in, that white matter pathology, and Max mentioned it also, cuts across a lot of neurodegenerative diseases -- neurologic diseases. And in fact, as we now have a tool to look for it, and I would argue we now have a drug that can treat -- potentially treat remyelination, I think that's the kind of -- those are the kind of things that allow -- will force us, force the biopharma community to begin to pay attention. And I think it's going to make a difference at the [indiscernible]. So...

All right. I think with that, we've had a couple of questions related to the Phase II timing and the number of patients assigned. I think we've talked about the 6 months. We talked about the 200 patients. I think we can -- RJ, what might be helpful is just to briefly talk about what we expect for the timing. And I think with that, we'll probably end the webinar, unless there's anything else that you guys would like to say.

Yes. I want to remind you that it is a very competitive clinical development environment out there. There's a lot of competition for patients. We have said publicly that we expect -- we would hope to be able to report data within 2 years of enrolling that first patient. Now you go 6 months, 2 years, wait a minute. Now remember the way it works. The day the first patient is enrolled, the clock starts ticking. The day the last patient is enrolled, you have to wait 6 months until you can basically lock -- start the database lock and analyze the data, let's say, takes another 3 months. So that's a full 15 months. And I hope to be able to tell you this thing enrolls faster than you can imagine. But we know how -- we would rather say it's going to take us 2 years and have it occur more quickly than to tell you I'm going to get this off -- this thing done in 18 months and have it take longer. So we -- our position is it will take 2 years. The good news is that we can -- the Phase III will be a fairly fast follow-on assuming we have the kind of data we're looking for. So just remember, if it was an 18-month trial, it would be a lot longer.

So I think with that, RJ, I'm going to pass it to you and CJ and Max for some closing remarks, if there's anything else that you would like to add. And with that, I think we've exhausted our time.

Max, any kind of final pearl of wisdom you want to treat everyone to?

No. I have to admit in my career, I've rarely seen such data. Although the ends are small, it's actually very impressive and exciting. It wakes me up at night.

Very good. CJ, anything you want to add?

Well, I don't think I can add above that. I'd like to thank Max for joining in and really spending time and working on this project with us. It makes a big difference. And I'll just say, I think you can see why we've been so bullish on this product for a long time. The animal data is very clear. And what we're -- the studies we designed are based on the biology we understand, and it translates remarkably well for small numbers of patients. So we are extremely excited to see if this translates into a clinical improvement. And so thank you for joining.

Yes. And I would like -- I know some of you are frustrated that we have focused so extensively on the science in our Phase I program, but I really want to emphasize that you really can't know enough about how your drug works. It prevents problems in Phase II. And as you know, if you fail a Phase II, you're done. So we wanted to make sure we design the most perfect Phase II we could. The other thing is everything we have learned can be applied to diseases of the brain where neuroinflammation plays a role, and that is a very wide net. You've heard of MS, ALS, Parkinson's disease today. We're interested in treatment-resistant depression. There are other neurologic diseases like PTSD. Someone mentioned TBI. I mean the list goes on and on. So in fact, we are laying a foundation of biomarkers and development strategies that we're going to be able to play and utilize over and over again. The only thing that's going to change is the disease. The biomarkers will be the same, but the diseases will be different. So with that, we very much appreciate your involvement today. We -- you know how to get a hold of us, and we look forward to talking to you. And Ian Pike and Max Descoteaux, thank you very much for being members of the panels. Thanks. Cheers.

It's a pleasure. Thanks.

Thank you, everybody.