INmune Bio Inc. (INMB) Earnings Call Transcript

Okay. Greetings, everybody. Welcome to the INmune Bio Webinar and XPro1595 Phase Ib interim data presentation. I'm David Moss, CFO of INmune Bio, and I'll be your host for this event. Joining me today are a distinguished group of panelists, along with Dr. RJ Tesi, CEO; and Dr. CJ Barnum, our Director of Neuroscience. A few housekeeping items before we begin. As a reminder, 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 this discussion. We expect today's call to last about an hour. About half of that will be allocated to the panel discussion, and the other half will be open for Q&A. [Operator Instructions] As a reminder, this conference is being recorded. Before we begin, I'll remind everyone that except for statements of historical fact, the statements made by management and responses to questions on this conference call are forward-looking statements under the safe harbor's Provision of the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties 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 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 to the date they are made as to the facts, circumstances underlying these forward-looking statements may change. Except as required by law, INmune Bio disclaims any obligations to update these forward-looking statements to reflect future information, events or circumstances. So now, with the forward-looking statements behind us, I'd like to introduce you to RJ Tesi, our Co-Founder and CEO of INmune Bio. RJ?

Thank you, David, and thanks to everyone for joining today. Until the COVID-19 pandemic, I like to say that Alzheimer's disease was the disease of our time. Soon, COVID-19 may be a thing of the past. This is not true of Alzheimer's disease. It is pervasive, relentless, disruptive and untreated. I choose the word untreated carefully. At this moment, treatment of AD is purely symptomatic. To make a difference, we need a disease-modifying therapy. Today, our collective goal is to stop the progression of this devastating disease. Once we cross that threshold, we will focus on the ultimate goal of reversing dementia. Today, we, as a company and as a discipline, take an important step forward. We will show you that XPro1595 decreases neuroinflammation as measured by a novel noninvasive biomarker called white matter, free water. Neuroinflammation is one of the not amyloid pathologies that contribute to Alzheimer's disease, and probably other types of dementia and other neurodegenerative diseases. Although our extensive preclinical data gave us confidence that we would decrease neuroinflammation, we were surprised and delighted to see such a clear signal in so few patients. Before we start, I want to remind you of the goals of this Phase I trial. This was a trial in patients that have biomarkers of inflammation who have Alzheimer's disease. The primary goal is to demonstrate that XPro can decrease neuroinflammation. We do not expect to show a change in the cognitive measures of Alzheimer's disease in this small 18-patient short 3-month trial. That will be the goal of the Phase II clinical trial in the near future. You heard enough from me for now, but let us let the data and our experts do the talking. With me on the panel are Dr. Rosalyn Lai, a psychiatrist and principal investigator at KaRa MINDS in Sydney, Australia. Rosalyn is an experienced clinical trialist in Alzheimer's disease, who has been actively enrolling patients into our study. Dr. Max Descoteaux is Professor of Computer Science in the department -- Professor in Computer Science at Sherbrooke University in Quebec. He is the CSO of Imeka, the company that has used their technology and what you will learn about to really refine these biomarkers that we find so important. Dr. Judith Jaeger is President and principal scientist of CogMetrics (sic) [ CognitionMetrics ], is a cognitive neuropsychologist and internationally recognized expert in accessing cognitive endpoints, and she has been immersed in the Alzheimer's space for decades. And finally, Malu Tansey, Director of the Center for Translational Research at neurodegenerative -- in Neurodegenerative Disease at the University of Florida, College of Medicine. Professor Tansey is an internationally recognized expert in neuroinflammation and neurodegenerative diseases, including Alzheimer's disease. And of note, Malu is an inventor of XPro1595's DN-TNF technology, and has been studying the drug's effect on neuroinflammation for more than 20 years. Also on the call is CJ Barnum, Director of Neurosciences at INmune Bio, and really has the primary lead responsibilities for this clinical trial. Before I jump into the data, I'd like to turn the microphone over to Dr. Rosalyn Lai to put this all in a clinical perspective. She's the one who is actually taking care of patients, sees their response. And I'd like her to relay that to you before I actually dive into the data and we get into a more scientific or talk about the what and why of neuroinflammation, XPro and Alzheimer's disease. Rosalyn?

Thank you, RJ. Thank you for the warm welcome. As RJ has mentioned, I'm geriatric psychiatrist by background and I'm a consultant, psychiatrist over at the St. George Hospital in Sydney. I'm also the principal investigator at the KaRa institute of neurological diseases in Sydney. As a researcher in dementia, it has been really exciting to be involved in the XPro trial. I've been so heartened, and I'll admit, I've been pleasantly surprised to hear some of the profound changes that some of our participants have been reporting. As you will appreciate, for people with Alzheimer's disease and their loved ones, who don't really care about the score of their mental or the progression of their confidence scales. For them, it's there day-to-day functioning and their capacity to engage in meaningful activity and experiences that give them pleasure and joy, that's important. So I'm going to give you a couple of the stories of change from our participants that are going through this trial. And hopefully, you'll be able to appreciate how remarkable this improvement has been for them. So the first gentleman I present, his -- let's call him, Andrew. So pretty morbidly, this gentlemen, he was a larger than life character. He was really social, gregarious, he was part of the Executive Board of a football club and a big movie buff. He's been suffering early onset of Alzheimer's dementia for a number of years. And when he came to us, he was really a shell of his former myself. He was very apathetic and socially withdrawn with very limited language use. In fact, his family would say that he would spend most of his day sleeping in his recliner. He'd need help with prompting for majority of his self-care tasks. Since being on this trial, he has had a gradual and steady improvement. His wife tells us that he's back to his old self, and he's regained his personality. He's brighter and more alert. He's interested, focused and he's engaging in day-to-day life. When he came to us, he hadn't watched television for 18 months, and he's started returning to watching the movies that he used to love. And he's also started to watch his football again, and has been engaging in conversations with his children and his grandchildren about how the footie's been going and who's going to make the next round. Socially, he's now able to hold a conversation. And more importantly, his sense of humor has returned, and his wife tells us he's cracking one-liners like he used to. From a functional perspective, he's now able to brush his teeth, dress and shave independently, which is remarkable. His wife even expressed surprise to us the other day that he pulled out his old aftershave, and he hadn't used this for years. When they reach the end of their 12-week trial, this family were willing to do absolutely everything to stay on this drug. They were willing to go to the TGA, which is your version of the FDA. They're willing to lobby politicians, go to the media because it was just such a huge change that they had observed in him. And they're really grateful that he's now in the extension phase currently. So Andrew is looking forward to one major goal in the future. One of his children is getting married in February, and he's really looking forward to being part of their big day. And the family are looking forward to seeing him there with his real essence returned. So that's been a lovely story to hear. The other gentlemen I'd like to present, let's call him Bob. He's a retired deputy principal of a high school, and he's got a background in pharmacy and science and he's a teacher of physics. He came to us on the milder end of the Alzheimer spectrum, having stopped work 5 years ago when he noticed that he was starting to forget the formulae that he needed to teach his students. Since being on his trial, he's telling us now, I've gone back to my usual life. He feels energized, motivated and his concentration and memory have improved. He's now able to recall physics formulae and far more. And he's even taken on a few students to tutor during this COVID time. He's gone back to reading academic journals, and he finds that he's not only able to understand the information that he's reading. And as for all of you who read academic journals, you'll recognize this is no easy feat. But he's also able to recall that information later. He's even started writing a book, which he had been considering for a number of years beforehand, but hadn't had the motivation or courage to start. So as you can see, for both of these participants, there's been a meaningful functional improvement that's occurred in quite a short period of time. So that's been super exciting to be a part of. So on that note, I might hand over to CJ (sic) [ RJ ] for a presentation of the neuroinflammation data.

Yes. Thank you, Rosalyn. That was very interesting. This is RJ, and I will now go through the data. And the forward-looking statements you've seen for quite a while. And on the first slide, I want to just remind you that this Phase I trial is a trial of Alzheimer's disease in patients with neuroinflammation. In other words, the goal, as I mentioned, is to decrease neuroinflammation, and we really don't expect changes in cognition. I mean, admittedly, the 2 vignettes that Rosalyn gave are really quite heartening. But we are really focused on neuroinflammation. And the way we're measuring that, that we think is most reliable is looking in the CSF, which is well tried, tested and validated. That data is not available today because it is batched for the end of the trial and by using a novel neuroimaging strategy with MRI. And that's what the discussion is about today. We believe that this MRI technology will revolutionize really clinical development in the field and ultimately, treatment of patients. Next slide. So we're talking about white matter, free water. White matter, free water can be measured by MRI. And you all know the gray matter of the brain. That's where all the nerve cell bodies are and where most people think the smarts reside. And then there's also the white matter. And the white matter is a very complicated structure with axons, which are really extensions of the cell bodies; myelin, which is the insulation; neuro cells, such as astroglia; immune cells, such as microglia. And when you start getting inflammation, you get swelling, just like when you get a splinter, and that swelling can be measured as free water in the white matter. And the beauty of the MRI, and Max will talk more about this, is it's noninvasive and it's quantitative. And it seems to be extremely precise and accurate. Next slide. In work done by the Imeka Group as part of their academic activities, you can see in this figure that free water and neuroinflammation increases from normal controls in the green, to patients with MCI in the blue, to patients with Alzheimer's disease. That is as the neuroinflammation progresses, the cognitive decline increases. And on the next slide, on the top figure on the left, you can see that with Alzheimer's disease, neuroinflammation in the red line continues to increase over time, which is different than MCI, which is where the amount of inflammation seems to remain stable but elevated of those -- of normals. For those of you that are comfortable thinking about amyloid, you'll be heartened to know that as the amount of amyloid in the brain goes up, the amount of neuroinflammation goes up as measured by white matter, free water on the right-hand side. Next slide. So how do we measure neuroinflammation? And as I said, Max will talk more about this in a moment. But to get through the data, I just want to give you a little brief background. White matter, free water is really measured in 2 ways using special sequences in the MRI. It doesn't require anything special but the software programs to help analyze the data that is routinely connected. On the left, you can see a global measure of white matter, free water. It's called the safe white matter mass, which is carefully calculated to exclude the fluid in the ventricles and around the brain. As you know, in patients with Alzheimer's that get a shrunken brain, there can be a fair amount of space between the brain and the skull. This is really a -- shall we say, a metric that is not as precise as the following metric. I like to think of it as sort of like measuring inflammation in the CSF. You can do a spinal tap, measure inflammation in the CSF, and you go, ah, the patient has inflammation. You don't know where that inflammation is, but you know they have it. On the right, you see the ability -- you see white matter tracts. White matter tracts are the super highways that connect parts of the brain in the white matter. And as Max explained it yesterday, he said it's like I-95 with 100 lanes. And these tracts can be imaged. The white matter free water can be measured. And because we know where the tracts, what parts of the brain these tracts connect, you might be able to make some predictions of what the pathology would be, and I'll come back to that. So first, let's look at the safe water -- safe white matter mask on the next slide. And as you can see in the middle bar, that the low dose group or the 0.3 dose -- David, no, David, back, back, back. Thank you. In the middle bar, the 0.3 group in the patients, there was over the 3-month period, there was a 1.7% increase in white matter, free water. In the higher dose group, and remember, an increase means the inflammation, the neuroinflammation is getting worse. In the higher dose group, neuroinflammation actually decreased. So there was a nice dose response between the lower and the higher dose. And to remind you, this is a Phase I trial that did not have a control group, but we took the liberty of looking at a nonconcurrent group of patients that have excellent data captured in what's called ADNI. This is the Alzheimer's Disease Neuroimaging Initiative based out of USC, and these are a group of Alzheimer's patients followed over time with both biologic imaging and cognitive assessments. And if you look at Alzheimer's patients followed over 3 months in general, they have a 5% increase in their white matter, free water and neuroinflammation. So we know that, in general, there seems to be -- XPro seems to decrease the amount of inflammation in the white matter. And quite frankly, we would have been happy to stop there, but the team at Imeka really has been crunching these data. That data crunching is not complete, but the next findings really caught our attention. Next slide. If you look at the white matter tracts that I mentioned earlier, the one that jumped out so far is called the arcuate fasciculus. Next slide. And in the arcuate fasciculus, you can see that there was a dramatic, a 40% decrease in neuroinflammation in the arcuate fasciculus, and that's compared to that 5% increase in the arcuate fasciculus that is seen in the ADNI cohort. Now in this group, there was no dose response. All patients had a decrease, the range was between 20% and 70%. So everyone went down. And that was interesting, but -- next slide. I have to say, 11 days ago, I had never heard of the arcuate fasciculus. Remember, I'm a transplant surgeon. I'm not a neuroscientist. So I had to really roll up my sleeves and dive into this area, and with the help of the panelists and CJ, I -- it became clear to me that we may actually be onto something here. The arcuate fasciculus is an important and a major white matter tract connecting the interior and posterior parts of the brain. And it happens to connect areas of the brain that are critical in language, and the role of language and the precision of language in patients and also short-term memory. So here, we have a situation where not only do we see significant decrease in neuroinflammation in a nerve tract that is shall we -- let's say, and I'll let the panelists talk about this more, seems to be critical in both the pathology, the clinical pathology of the disease. And may give us a clue on where we should be focusing our efforts on measuring responses to the drug when we do the Phase II trial. Next slide. So in summary, this is a small group of patients. I'm the first to admit that. We have 3 in each group. But the results are impressive enough to give you pause, particularly when you hear the stories that Rosalyn tells. There was clear dose-dependent reduction in the, shall we say, the whole brain white matter neuroinflammation, measuring using the safe mask free water. But what really caught my attention as a clinician, or at least as a drug developer, a clinician turned drug development professional is the 40% decrease in the arcuate fasciculus. That is to say that, as I mentioned, you now have a structure that seems to be critical in the clinical pathology of the disease, both the diagnosis and progression of Alzheimer's disease because of the role of language that this drug seems to really change the amount of inflammation in that pathway. So with that, I'll stop. I'll put up the next slide because it is -- I'm going to ask really Maxime to really talk about a little more eloquently than I can, the use of MRI to diagnose white matter, free water as it relates to neuroinflammation. And also talk about the power, the other powerful measurements that they can make in white matter. Maxime?

Yes. Thanks, RJ. It's an honor to be here. Just so -- just a quick word about these scenarios. I love these little figures here. If you go from left to right, you go from a healthy white matter microstructure environment with what you see here, cylinders represent axons surrounded by myelin, surrounded by cells that make sure that the myelin components are functioning okay. So oligodendrocytes, microglia, astrocytes. And with pathology and especially neurodegenerative diseases, 1 of the 3 scenarios or all of the 3 scenarios behind after can occur. And 1 of which is no inflammation where you see -- and this has been shown in a lot of animal models and measured with microscopy. You see an increase in extracellular space, a bit like when you hit yourself and you see edema and you see a bruise on your leg. While this is thought of being something similar but around the white matter tissue in your brain. So you have an increase of water there. And diffusion MRI is really sensitive to this. We are imaging the white matter through looking at how water molecules navigate in this environment. As if you were driving your car on highway 95 and you get to a traffic jam or you get to a construction block or a big pothole, you will drive around it or you will make actions that could be detected by satellite, for instance. So it's kind of the same analogy, but our satellite is the MRI machine and the car driving on the highway is the water molecule. And so this water molecule leaves the signature in our images, which is undetectable by eye, by the neuroradiologist, but detectable with a bit of modeling and sophisticated analysis, which is not all that sophisticated. But essentially, we can capture this amount of free water. And that's what RJ has been telling you about. So this second figure. And what's exciting is once you do that, you can also start capturing how much axons are actually lost or what is part of the myelin sheet that's disappearing because all of these phenomenon affect how the water molecule navigates in its environment. And so using the same type of acquisition that is a 5-minute MRI acquisition, we can extract these 3 meaningful novel indirect markers of inflammation, axonal depth or demyelination. But for today, the focus is neuroinflammation. And I'd be happy to answer questions later about the technicality, but let me send it back to you, RJ, if that's okay. You muted, RJ.

Malu, you've spent your career actually dragging the concept of neuroinflammation into everybody's forebrain, so to speak. And certainly, with XPro, you obviously are one of the major contributors to the scientific literature. And what do you think about this whole concept of white matter, free water and actually, white matter disease in general as it relates to Alzheimer's disease?

Yes, that's a great question. So one thing to bring up is there've been some studies actually done at my new institution at University of Florida by a colleague, David Vaillancourt, in which they measure the free water changes in white matter in models in which might have been injected with interferon gamma. And they see these changes in free water and white matter due to inflammation, which actually ties in really nicely in the preclinical space to some of the changes that you guys see. And they've also seen these free water changes in patients with early Alzheimer's and MCI. So I think the changes that you're seeing are definitely happening due to changes that experts is likely to be inducing an inflammation. And we've seen them in over 90 publications now. So it's really exciting, and it's hard not to get really excited about the years of preclinical work that has [ lead ] to this, which is super exciting for everybody, a lot of people. What I would say about why the myelin is -- there's a lot of reason to think that maybe this disease doesn't necessarily start with neurons getting sick. There's a lot of evidence that maybe microglia are stripping synapsis and maybe stripping myelin away somewhere where they shouldn't be. And maybe that's where the inflammation is happening. And so we need to maybe shift our thinking in that not everything is happening at the synapse, and maybe there is some myelin changes happening. [ Carl Harrop ] has some interesting ideas about the role of myelin and some changes that need to be taken into account, oligodendrocyte, health and other things that are happening. So this is really exciting. And I think it should lead us to less noncentric and more real dysfunction and maybe some of the genetic changes and genetic hits that are coming up in the meta-analysis of Alzheimer's risk, low sight, should lead us to think that we need to look elsewhere and not just in terms of neuron. So this is super exciting.

Thank you. Judith, as someone who has been involved in diagnosis and shall we say, scoring or -- of Alzheimer's disease for many years, I mean, in the past, we've always had turned to you to do testing to, so to speak, look from the outside in, trying to understand how the symptoms affected the neuropathology. What Imeka's team has allowed us to do is look from the inside out. In other words, we've identified pathology in the arcuate fasciculus. How does that change the way you think about how you should be testing or studying these patients? Or does it not change your thinking at all?

Well, it actually aligns very nicely to some work that we've done, where we've had findings related to language that had not been anticipated. So there are a number of efforts to develop a preclinical Alzheimer's cognitive composite or pack. And I was involved with 1 that looked at 4 different cohorts and was entirely data-driven where we simply use statistical methods to ask the data set. Now these are longitudinal cohorts that have followed healthy adults for 3 to 5 years where we have measures of amyloid. So we can classify people as amyloid positive clinically normal or amyloid negative clinically normal. And we look at the trajectory of their performance on annual cognitive tests. And using 4 different cohorts independently, we have confirmed an earlier suspected finding that among the measures that are sensitive to that progression, again, within the normal range now, it's the progression associated with amyloidosis is verbal fluency. And when I saw these findings, that's the first thing that occurred to me because, of course, the disconnection syndromes of the arcuate fasciculus are classic in neuropsychology, it was not an unusual -- it was not an unknown tract to me because there was a literature on this in the past that showed that in lesion studies, these are the kinds of deficits you can see. So this is fascinating to me because it provides for an explanation for a clinical finding that I really hadn't thought really hard about what would be the neuropathology underlying because, of course, we think of this classically as a hippocampal disorder, which we, of course, know it's not. But in the earliest stages, that's how we think of the earliest presentation. So this is remarkably consistent with our clinical findings about what are the factors that are associated with, that is to say, the cognitive operations that are seen to decline steadily in the earliest stages of this disorder.

Thank you, Judith. CJ, on the slide that's up now, there are these other 2 areas, the accidental death and the demyelination, which also can be measured as part of the technology that Imeka brings to the table and, Max, jump in here also if you feel appropriate. Will we be looking at that? And do you have any expectations that we'll actually be able to take this holy trinity of inflammation, neurodegeneration and demyelination, and actually apply it in our patients as we study them after treatment with XPro for Alzheimer's disease?

Yes, it's a great question. The -- and this is the reason I really like the technology that Imeka has developed and that Max here has been a pioneer of because it allows us to do a variety of different analyses with a simple, noninvasive scan that -- and, Max, correct me if I'm wrong, is -- deviates very little in terms of time and the way the machine is set up based on what's currently done. So I think the neuroinflammation story is extremely exciting. But I think where we can go in the future, start looking at these biomarkers of neurodegeneration that have only been available post mortem or with some other assays. So right now, if you want to measure neuroinflammation, axonal loss and demyelination, you need at least 3 different assays. So we can measure neuroinflammation via CSF, which is sort of the classical way to do it. Axonal death is routinely measured by neurofilament. Again, that's CSF. We're doing it in the blood. And demyelination requires an MRI. And what we're seeing here is we can capture all these things in a single measure at a single time point and do some really interesting analyses. And I think you can see the power of this particular metric based on our ability to locate and isolate a particular region of the brain. And I'll go back to what Judith said. I think from my perspective, this is extremely important because now it gives us an opportunity to tie the biology to a specific outcome and allow us to develop clinical outcomes that mirror where you're seeing changes in the biology. And so this is the beauty of the composite scores and that sort of thing. So I think this is going to be extremely valuable moving forward as it relates to clinical development and planning Phase II and beyond.

Yes. Malu, I'm going to ask one more question and then turn it over to the Q&A, but you've been -- you were a pioneer -- well, let me step back. You can remember, when I first got involved with the drug with you in 2011, there was this raging debate of whether you could use a protein therapeutic to treat a CNS disease. And in fact, I'll remind everyone that this drug is given as a once a week subcu injection. So actually, peripheral administration is having central effects. And Malu, your team has really pioneered this concept of is it peripheral inflammation that's causing central inflammation? Is it central inflammation that needs to be treated? Is it both? Or how do you put this all together? And does it really matter if you're getting clinical responses?

Right. No, that's a great question. And so for those of you that aren't as familiar with the drug, this is a biologic rate. And so unlike other biologics, it is small enough and it is such that it does cross into the brain. And it is also selective for the soluble form of TNF, which is important because it is only dampening inflammation, and it's not targeting any of the functions of membrane-bound TNF that suppress protection against infection or myelination. And so what's important here is that you're going to be targeting inflammation peripherally or centrally, right? And to the extent that anything in the periphery is affecting your brain, then we need to know about it, and we need to target it. And so it was thought that your brain didn't know what was happening in the periphery. And now, we know that's different because diseases like obesity, metabolic syndrome, diabetes are apparently, at least epidemiologically, risk factors for a lot of these neurodegenerative diseases. And so we think that what happens is that either through leaky gut and leaky BBB and maybe changes in microbiome, unhealthy living, unhealthy diet, physical inactivity, there's a change in the conversation between the central and peripheral compartments in the way that the circulation and the crosstalk between the peripheral immune system and the brain immune system function, and so there are changes. And when you change that conversation either through the dynamic of the BBB and the gut, brain abscess that you can affect changes by changing that conversation. And so XPro through many, many preclinical studies, not just in our lab, has been able to change that conversation, either directly or indirectly, either by changing the cytokine profile, by changing the innate and adaptive immune traffic from the periphery into the brain. And also by changing changes in microbiome, there's a few studies more recently that have shown that. So we don't know exactly all the mechanisms that are involved, but we do think that by changing things in the periphery directly and indirectly, there are changes in the brain that change the physiology and also change the behavior of the organism. And so there are other studies by Clive Holmes and others, through some studies that are published actually, with other drugs that don't cross into the brain that do show that changing the inflammation peripherally can also affect changes in the brain. So there is some communication that's very well established.

So thank you, Malu. I think in the interest of allowing some Q&A, I'd like to kind of stop the panel discussion and really go to the questions. And really, I expect the panelists to be answering most of this. So I would ask the questioners to really take advantage of this -- our guest group that we have on the phone. I mean, you can ask CJ, David and myself questions any day of the week, but these are the smart guys, and you don't get access to them very much. So take advantage of that. So David, back to you.

Thank you. [Operator Instructions] So our first question is from Jonathan Aschoff over at ROTH.

Congrats on these results thus far. My first question is, what makes the ADNI cohort comparable as a clinical trial control group? How are they matched, if at all?

On major...

CJ or Max?

Yes. Well, right now, we're taking -- they're not matched at all, but so we're assuming that they're age matched. We took the 25 subjects part of ADNI, with the time points that are comparable with the current Phase Ib trial, that is subjects with patients with a baseline at 0 and 3 months with good quality diffusion MRI scan that passes quality control. And so that's our baseline and that's our control group that we've analyzed. So -- and the acquisition scheme is very comparable. And in the ADNI, for instance, this is really run like a clinical trial type acquisition because acquisition is difficult. This is not cutting-edge research acquisitions. It's really standard clinical press button at the MRI.

Yes. Jonathan, I'm not going to argue that it's not a perfect control group. The trial was not designed with a control group. But I would ask you to focus on -- or I'd ask everyone to focus on the 40% decrease in the arcuate -- of inflammation, in the arcuate fasciculus. I mean, this wasn't accidental. It's in response to the drug, every patient underwent it. And I think the clinical vignettes that Rosalyn provided, language was an important part of that clinical vignette. So even if you strip out the ADNI, if that's problematic in your thinking, understanding that this is early, it's a small sample, but it supports exactly what we saw preclinical, exactly what Rosalyn is showing in her patients. And now, it's up to us to prove that to everyone's content using with more patients.