INmune Bio Inc. (INMB) Earnings Call Transcript

Okay. I think it's time we get started. I appreciate everybody joining us today, and we're very excited today to talk to you about our new program in treatment resistant depression. So welcome to the INmune Bio's KOL webinar on treatment resistant depression, or TRD. I'm David Moss, CFO of INmune Bio, and I'll provide our listeners with an outline of today's event. Before I turn it over to our moderator, Dr. CJ Barnum, who is our Head of Neuroscience for INmune Bio, who will introduce our very distinguished group of panelists here today. 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 the close of the discussion. We expect today's TRD XPro1595 webinar will last about 1 hour with about 45 minutes of the time allocated to panel discussion and the rest for Q&A. [Operator Instructions] As a reminder, this conference is being recorded. Before we begin, I remind everyone that except for statements of historical facts, the statements made by management and responses to questions on this conference call are forward-looking statements under the safe harbor 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 such as forward-looking statements. Please see the forward-looking statements disclaimer on the company's earnings press release as well as the risk factors in the company's SEC filings, including in 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. So with these forward-looking statements behind us, I'd like to introduce you to your moderator, Dr. CJ Barnum. CJ?

Thank you, David, and thanks, everyone, who is joining today. David, if you could advance to the next slide, please. I'd like to start with a slide that puts this program that you're going to hear about today in the context with the overall company platform. So INmune Bio is a company that is developing therapies to treat the innate immune dysfunction. As this figure depicts, innate immune dysfunction participates in the pathogenesis of many diseases and our ongoing clinical programs in cancer, Alzheimer's and coronavirus illustrates the breadth of this problem. Now thanks to an award from the National Institute of Health, we now add major depression to our clinical programs. Next slide, please, David? Major Depression is a debilitating disease that is extremely common. Approximately 25 million patients suffer from depression and is estimated that 1 out of every 5 people will have a depression episode at some point in their life. Major depression is also one of the leading causes of death and is the leading cause of disability worldwide, which you'll hear more about this shortly. Unfortunately, approximately 7 million patients do not respond to conventional antidepressant therapy. It is the goal of this webinar to provide some context around this problem and why we believe targeting inflammation could provide significant benefit for many of these patients. We are honored to have with us 2 extremely highly regarded thought leaders in this space. And the bios that I'm going to give you will not do them justice. Dr. John Schneider is the CEO and Founder of Avalon Health Economics. Dr. Schneider has over 25 years of experience in this area and his company is a full-service health economics and outcomes research organization with considerable experience in treatment resistant depression. Dr. Charles Raison is the Mary Sue and Mike Shannon Distinguished Chair for Healthy Minds, Children & Families at the University of Wisconsin, Madison, among many other places. Dr. Raison is one of the foremost experts on inflammation and depression, and he is uniquely qualified for this discussion having published the seminal proof-of-concept study showing the efficacy of anti-TNF treatment for treatment resistant depressions, a story you'll hear more about later as well. Thank you both for being here today, and we are very much looking forward to your talks. So the agenda for the remainder of this webinar as follows: Dr. Schneider will give you a presentation on the economics of treatment resistant depression; followed by Dr. Raison, who will talk about inflammation and the precision treatment of depression. After that, I'll talk a little bit about the clinical trial, and we'll have a Q&A. So with that, I'd like to turn it over to Dr. Schneider. Dr. Schneider, the floor is yours.

Thanks a lot, CJ. I appreciate the introduction, and thank you to everyone who's joined us today from around the world, I guess. And originally, I was going to go after Chuck and thankly, he's a tough act to follow obviously. So thankfully, I got moved ahead and anything you have to ask for that. So thankful for that. Yes, there's nothing much more I can add to my bio, except that this has been an area that I've been interested in for a while. I started to do some research at the University of Iowa on sort of organizational factors around MDD. So that's what got me interested in and that was about 20 years ago. So I've been doing some work ever since. So I think, CJ already mentioned some of the sort of basic highlights around MDD, and it is about 8% of the population. There's various estimates out there that have it at more than that and some that have it a little less than that, but that still quite a high prevalence. And perhaps more importantly, the prevalence of major depressive disorder has been growing. And it's expected to worsen, there's been some early studies out showing evidence that it's expected to worsen as a result of the pandemic and the resulting recession around the pandemic, largely due to things like stress and job loss and lower wages and things like that. MDD, again, as CJ mentioned, MDD is associated with significant morbidity, mortality costs, work loss days in the form of absenteeism and productivity in the form of presenteeism. These are very substantial factors associated with MDD. Now a substantial proportion of the pharmaceutically treated depression, or PTD, patients do not respond to treatment with 2 or more antidepressant medications despite adequate dose duration and adherence to treatment. These cases are generally considered treatment resistant depression, or TRD. The proportion of MDD/PTD cases that progressed TRDs is estimated anywhere between 10% and 35%, depending on the study and the definition of TRD. Some estimates are as high as 50%. Meta-analysis that we've conducted show it to be around 13% to 15%. So this is a big problem. You've got these cases that of MDD who are not getting better and progressing to treatment resistant stage of disease. So TRD, how -- the question that mainly that I'm going to focus on is how expensive is TRD? What are the economics of TRD? In terms of direct and indirect costs -- and this chart, this is from AMOs et al, I think I can't see the bottom of my slide here but I think it's a 2018 study. This is a chart that shows TRD, the columns sort of from left to right here, are TRD, non-TRD, MDD and then non-MDD. So the main point here is that you can see the TRD incremental additional cost is significant. It has comparatively high mental health costs as well as non-mental health care costs. That's the sort of reddish shaded figures, red and pink shaded figures are mental health related and the blue are non-mental health related. You can see that they're both higher for TRD versus non-TRD, MDD. And of course, both of those are higher than non-MDD. So the important message here is that it's -- we're not just adding mental health care costs, we're adding sort of regular health care costs as well when we progress to TRD. And if you go over to the right-hand side of this, the figure -- well, I'm sorry, can you go back to the other -- yes. The right-hand side of this figure shows that TRDs also has substantially higher disability costs. So that's the lighter color, sort of aqua color there, the lighter color is the disability costs. And those are also higher for TRD, substantially higher. Move to the next slide. Now what this shows is, this is a study by Pan et al. This shows that even within TRD, there are significant differences. So not all TRD is heterogeneous. So in this case, severe TRDs associated with higher -- it's mainly higher behavior-related costs than moderate TRD. And both of those are higher, both in terms of non-behavioral-related costs and behavior-related costs compared to the mild TRD. So again, this part of the problem in defining TRD relates to this type of heterogeneity. Next slide. One of the things that's common to TRD is that it's associated with changes in treatment regimen. So -- or I should say the cost of TRD associated with changes in treatment regimens. These are 2 different studies here. Interestingly, I thought that these studies are use data that are 15 years apart. So the study on the -- on your left by Russell et al shows that the horizontal access toward number of antidepressant medication regimen changes. And so it goes from 2 to 8. And then the horizon -- I'm sorry, the vertical access is dollar per month. So you can see that there's this linear trend here of costs increasing with regimen changes. So every time you change these medication for the treatment resistant patient, they're incurring more costs on a dollar per month basis. 15 years later, studied by Amos et al, actually the same study that I referenced and discussed above, essentially shows the same thing. And this is number of lines of therapy of adequate dose and duration across the horizontal axis. It goes from 2 to 6 plus. And then the vertical access in this case is payments per patient per year or expenses per patient per year. So again, you can see this linear increase. The advantage of this chart is that we have -- well, actually similar to Russell, but in greater detail, the breakdown of non-metal health care-related costs and mental-related costs. And once again, we see both of them increasing with regimen changes. Next slide. So one of the main points here, well, just to run through the main points. TRDs, at least twice more costly than MDD. That's what Amos et al found and some other studies that reach similar findings. So 2x more costly. We also know that more severe TD is more costly than mild TRD. So we have, again, this heterogeneity within TRD in terms of severity. TRD patients who switch regimens more frequently have higher costs than those who stick with the regimen for a longer period of time. So what are some challenges here? There are obviously a lot of them. One is how to define TRD? There's some debate about that. And the other is how to determine which patients are more likely to progress to TRD from an MDD state or progress within TRD from a mild state to a more severe state? Again, the range of patients progressing to TRD is estimated to be between -- essentially between 10% and 50%, if you look at the whole range of the literature, again, it's a big range. So there's likely within TRD, a treatment heterogeneity problem. And that's something that could be addressed with biomarkers. If you look at -- just to describe what I mean by a heterogeneity problem, one of the things we face in pharmacoeconomics quite often is this idea of treatment heterogeneity. And generally speaking, what it means is that there are some treatments that work better on some types of patients and not so good on other types of patients. The way to illustrate this is if you look at -- this is just a simple diagram. It doesn't pertain to any particular product or drug. What we have here is the treatment effect on the vertical axis. And across the horizontal axis, we have distribution -- sort of a hypothetical distribution of patients. So you can think of the distribution A would be a randomized clinical trial of drug X on all individuals with disease wide. This is sort of your classic RCT, randomized clinical trial design. In the curve Label B, you have an RCT on -- of X, Drug X on patients with Y disease, but perhaps for only age over 50. So what do we see here going from A to B is that we see a higher treatment effect for the overage 50s. I mean this is sort of what I'm talking about when I mentioned treatment heterogeneity. You've got a bigger -- more bang for the buck, if you will, by treating the patients in Group B rather than in A. And finally, in Group C, again, this is all hypothetical. You can do an RCT of X on Y with specific biomarker of Z. So you have some biomarker that indicates somehow which patients are going to be more responsive to treatment. And when you do that, you can have a greater treatment effect. Now if you see the note below, that says the areas under the curve would be different. So A would be the largest B would be the next biggest and then C would be the smallest. So you're getting a larger treatment effect for a potentially smaller segment of the population. Now that's not always true. You can have a biomarker that doesn't necessarily limit things very much. But generally, that's the idea is that you're using the biomarker to search for those patients who have the highest treatment response. So this is something that I think could have some value in a condition like TRD. I think that's my last slide. I will pass it on to Dr. Raison, who has a very interesting take on -- do a deeper dive, I guess, if you will, on TRD.

Yes. Thanks, John. And Chuck before, let me introduce you. The complexity of the problem in trying to segment these patients, I think, is really important. It's something that's been lacking. And really, Chuck, what I really want to know is, do you have any ideas on how we might do that?

Well, sure. I mean, it's fascinating that the most promising biomarkers by far in depression, which we always think of as sort of a neurological kind of brain disease are actually markers from the immune system, and that's what we'll talk about. David, you know what? I'm worried that if you give me control, I may not be able to give it back to you.

Okay.

So to control with you, and I'll just say next. So anyway, hey guys, and folks, it's nice to talk to you. I have spent a lot of time in this space. It's one of the most fascinating and powerful developments that's happened in mental health over the last 15 to 20 years. So inflammation in the precision treatment of depression, let's dive on in, if you can hit next. Well, so let's start with the thought experiment. So here we see a gentleman outside of a house. And the question is, does he look like this because he had a girlfriend or a wife in that house, who threw him out and he's heartbroken? Or does he look like this because he ate some bad fish and he just threw up in the bushes? And it really highlights something that is -- that was really the start of this feel, which is, if we can have next, please, that depression and sickness look a lot like each other. This was first actually discovered by Robert Dantzer in mice, but you see the same thing in human. So if you line up what happens to us? When we get sick versus what happens to us? When we are depressed, the symptoms are largely overlapped, right? So when you get sick, you lose pleasure and things. You're exhausted. Your appetite changes. Your sleep changes. You have a hard time thinking. You can feel down. A lot of people feel down. You're tired. You slow down. You just -- there's a whole list of them here. Well, it turns out that if you cast an unbiased eye on major depression, you see a lot of the same symptoms. In fact, the overlap is quite striking even on things we don't think about as being related to depression. So the classic symptom of sickness, god knows, as we know now in the age of COVID is fever. And the reason you get fever and other symptoms when you get something like the flu or COVID, it's not that the virus goes up to the brain and sort of tinkering with your machinery, it's that the body's immune system recognizes the virus is something dangerous, activates these inflammatory pathways. They signal the brain to raise your body temperature, to make you tired to do all these things, to cause sickness because over evolutionary time sickness helps you battle infection. So it turns out, for instance, the fever exists because higher body temperatures tend to denature viruses and bacteria, and they also activate the immune system. Well, we always think about depression as being primarily related to inter personal sort of social or psychological issues, but there is a robust literature showing that if you take medically healthy people with depression and measure their core body temperature, it is elevated. And if you treat them successfully, their body temperature falls. It's really quite remarkable. So even symptoms like that suggest there's some sort of deep correspondence between sickness, which we know is driven by inflammation and depression, at least in groups of people. Next slide. Well, so that was actually the initial observation. The next major thing that happened were that a number of us began to realize that there were -- think there were medical procedures that were being done in the '90s and into the 2000s that could serve as remarkable model systems for understanding in human beings. What happens when you take somebody that's not inflamed and artificially inflamed them? And the most classic of these model systems was a drug called interferon alpha, which is a cytokine. It's a molecule produced by the body naturally in response to infection. But it was widely used for cancer, it didn't work that well and more widely used for hepatitis C, where it did work pretty well. But it had this remarkable property that you took people. And when they started taking the interferon, they begin to show signs of inflammation. Next slide. And so it was none other than Andy Miller, who you'll hear about that is my old mentor and colleague at Emory, who's one of the coinvestigators on this grant that the company has gotten for EXPAREL, who had the really great idea of looking to see how often do people that are getting interferon alpha go from not depressed at all to really depressed. So he rounded up a bunch of folks that were starting interferon alpha for malignant melanoma. They were not sick. They were not depressed. You can see down is bad on a slide like this, times across the bottom, 12 weeks. And what he found was in this group of -- except for having a melanoma that was problematic but not being sick and not being depressed. By the time 3 months of this chronic inflammatory stimulation from interferon alpha was over, 50% of them had a raging major depression. Now the reason this paper got into New England Journal of Medicine, though, was that he did something even more interesting, which was 2 weeks before people started to interferon alpha. He started half of them on an SSRI antidepressant, an antidepressant called Paxil, which is widely used or a placebo, blindly, people didn't know what they were getting. They took that for 2 weeks. They kept taking it, and they started taking the interferon alpha. And what he found was that if you could hit the next slide, please, or the next thing, that the red line, the people that were pretreated and stayed on that regular old antidepressant had their rates of depression reduced by a factor of 3, a massive effect. So here is evidence that's been just replicated repeatedly since then, that you take people, you put them under a chronic inflammatory stimulus. They have a real high rate of getting depressed. Looks like depression smells like depression. You treat them with a regular old antidepressant and boom, you can really attenuate that development. So this really suggests that inflammation is involved somehow in the pathophysiology of depression. So if you can hit next, please. So Andy and I followed up on this in a series of studies with interferon alpha in hepatitis C patients. And this is one of my favorite findings from those studies. We studied these guys up one side and down the other. We brought them in before they started interferon. We measured their sleep. We measured their blood. And here, we measured their body's immune response to their first shot of interferon. So they got the shot. We measured their blood levels of cytokines, and in this case, a very important inflammatory mediated within cells called P38 before they've got the interferon and for hours and hours afterwards. And this is a really remarkable finding. So we found out that we could almost 100% accuracy predict how depressed people were going to be a month later. So after they've been on interferon alpha for a month, we could accurately predict it by how much P38 they made within the first 6 or 7 hours after the very first dose. So what you can see here is the differences in P38 production over on the left, on top between people who went on to be depressed, getting interferon alpha versus people that went on to get a lot less depressed even though they were on interferon alpha. The scanner graphs below just show it's just amazing. The more this inflammatory P38 goes up in the first few hours, the more depression goes up over a month. Now interestingly, when we looked at P38 a month later, so when we looked at it at exactly the same time spot as the depression ratings, there was no correlation. So this suggests P38 boom gets activated right away. It's doing something. So what does P38 do? Well, one of the main things it does is it turns on a cytokine that's directly relevant for the conversation we're having today called tumor necrosis factor alpha, or TNF. It's one of the great sort of major inflammatory cytokines in the body, along with another one called Interleukin-1beta. So it turns on TNF. Do people that are exposed to this chronic inflammation, do they have elevated TNF when they're getting their interferon alpha? Next one, please. Yes, they do. So the graph on the left shows people treated with interferon alpha that have HCV, hepatitis C versus a control condition group that did not get interferon alpha, but that had hepatitis C. The purple line is way higher. So across 24 hours, we got blood every hour. The people that were -- that had spent a month of receiving interferon alpha had much higher levels of one of its primary receptors that is key for driving its inflammatory signaling. Even more interesting in some ways, if you look at the scatter plots on the right, what they say is that the more your interferon -- the more your TNF went up in response to interferon alpha, the more exhausted and unhappy you got. So it's a very sweet story. Interferon alpha is a driver of inflammation. It activates some early mechanisms that turn on TNF. The more TNF you get in response to interferon alpha, the more miserable and depressed you are, really suggesting that blocking TNF might have powerful antidepressant effects. Next slide. Well, so what we've said so far is that if you inflame people on average, especially when the inflammation is chronic, they get depressed, and it's got something to do with activating TNF because the more that inflammation activates TNF, the more depressed people get. Do depressed people as a group, have elevated TNF? And the answer is definitely, yes. This is a meta-analysis. When you put studies together, it's very clear that groups of depressed people have increased inflammation. TNF is the third most often replicated immune biomarker that's elevated. The 2 that are most reliably elevated are CRP, C-reactive protein and a cytokine called Interleukin 6. The reason that they are more often observed is because they circulate at much higher levels in the blood. TNF doesn't get into the blood very much. It's mostly sort of within cell kind of thing. But nonetheless, there's a signal that is consistent. So groups of depressed people also show elevated TNF. And you can see how the story is beginning to evolve here, but there's a wrinkle. If I can have the next slide. Oh, now before I get to the wrinkle. So there's been a lot of talk in the last few years that maybe depression has something to do with the modern world. And it probably does. But there's this idea that, hey, before modernity, everybody was happy in life as a sort of garden variety. Not true. And one of the ways we know it's not true is there's a group of anthropologists from the University of New Mexico who wanted to study our hypothesis that depression had evolved out of sickness, the depression helped people survive infection in ancestral times because it was associated with increased inflammation. So they went down to a group of semi hundred gatherers called the Tsimane in the Amazonian parts of Bolivia. And they -- first, they look to see whether they were depressed people. Sure were and the depressed people were depressed for exactly the same sort of things we get depressed about. They're depressed because his wife left him for the guy in the next hut, that kind of thing, right? They also measured their blood to look at inflammation. And if you can hit next, they found that just like in our world, the depressed people had elevated inflammation, in this case, elevated IL-6 in particular. So it does look like this association between depression and inflammation is not a quirk of the modern world, it's ancient. It's somehow integral to the -- to what depression is. Next slide. But there is a wrinkle, and here it is. So these are actual data from a study of stimulated IL-6. The control group, look at them in orange. And what's interesting is they're all kind of bunched together at a low level. What you see in green are the folks with depression and look how much more scattered out they are. They have a lot more variation, and there's a whole bunch of them that don't look any different than normal. So if you can hit next, you'll see that there is a -- next, there is a group that we might consider as an inflammatory subgroup that clearly have levels above what you see in the normals. Next. And then there's another group that you might think of as a noninflammatory group that looks like the normal folks basically. The reason that the depressed people have increased inflammation is not that every depressed person has a little bit of elevated inflammation. It's that there is a subgroup. There is a group of people within the depressed population that has really significantly elevated inflammation. Next. Well, so these findings were available in the mid-2000s, and Andy and I decided to really put our money where mouth -- put our mouth where the money was or the other way around, if inflammation causes depression, if depressed people have increased inflammation, blocking inflammation should show an antidepressant effect. So how are you going to block inflammation? Well, things like aspirin and ibuprofen, they block inflammation, but they also have all sorts of other effects that might influence either them making people less depressed or more depressed, frankly. So we wanted something that was pure, something that all it did was block one of these key inflammatory cytokines. And we eventually settle on a drug called infliximab, which used to be marketed as REMICADE. It is a nonspecific TNF-alpha blocker. It's an antibody. It just wipes out TNF, in general. So we took people that were medically healthy but had treatment resistant depression, TRD, just like John was talking about. And we randomized half of them to get 3 infusions of saltwater and half of them to get 3 infusions of this very powerful cytokine TNF blocker infliximab. They got one at start. They got one at 2 weeks. They got one at 6 weeks. And we followed everybody for 12 weeks to see -- to show 2 things. First of all, to show that if you block inflammation as a group, depressed people would do better; and second, that the higher your inflammation was before you started getting the anti-inflammatory TNF blocker, the better of an effect you'd get because of inflammation is causing your depression. The higher it is, the better you should respond to blocking it. That just makes sense. So what did we find? Well, this is one of the challenges of depression studies. We were about 2/3 of the way in, and we were seeing all these miracle cures. Man, I mean these people have failed multiple antidepressants. And they were saying, "Oh my God, this is a miracle cure. I'm going back to work. I've never felt better. So we were utterly convinced that we were going to become world famous as the discoverers of a new general purpose antidepressant agent because there was no way that saltwater could have that kind of effect. If you could hit next. When we broke the blind and looked at the data, in fact, we found that saltwater had exactly that kind of effect that in the population as a whole, there was absolutely no difference between infliximab, and saltwater. And then numerically, in fact, saltwater was a little bit better. If you had some ocean front property, you could invest in seawater. And if you inject it in the right way, it has a powerful effect, speaking to the power of placebo, which also speaks to the need to identify biomarkers for people who are going to have less of a placebo response and more of an active biologic response to your agent. Next slide. Well, so that was the first -- that was our first theory. It's not a general anti purpose, all purpose antidepressant agent. What about whether people with increased inflation had a better response. And if you hit next. Here, we -- the data, we saw this no matter how we cut the data. Here, we're just looking at whether people had a response, a clinical response or not to the agent, which is a 50% reduction in their baseline score. Blue is infliximab, orange is placebo. The bars on the right that I've circled are people that have elevated inflammation. You can -- you see this effect, whether you look at it by C-reactive protein or whether you look at it by TNF, tumor crest factor alpha levels beforehand. This is the CRP data. These are the CRP data. And what you can see is that in that group, the blue bar is way better than the orange bar. And it is much better than the orange bar as regular added depressants are compared to placebo. So if your inflammation is elevated and you're depressed and you block inflammation, you get an anti -- specific antidepressive response. So why were the groups so equal to each other in the entire population? Well, this is also an argument for the specificity of this immune inflammatory blocking effect. Look at the bars over on the left. These, in fact, are the 2/3 of patients that had lower levels of inflammation. The lower the levels, the less of the benefit they got from infliximab and the more of a benefit they got from placebo. So should those guys did way better with saltwater, and you don't want to block their inflammation. So look at the orange bars. As your inflammation goes up, your placebo response drops. So there's 2 fascinating things here. It suggests that if you use an inflammatory biomarker and you use a powerful anti-inflammatory agent, not only do you get a specific effect in that elevated inflammation population, but you get less of a placebo response rate, which has been the devil of adding depressant studies because it tends to wash out specific effects. So it's a perfect marriage in these high inflammation individuals, you win on both counts. Next slide. Well, so this study was replicated or tried to be replicated by kind of a super dude -- famous dude student in our field up in Canada, named Roger McEntire. He took bipolar depression. He replicated our study with one caveat. These are folks in Canada. They're thinner. They're in better shape. He did not -- he had a very hard -- he had a harder time finding people with elevated baseline inflammation. So his baseline inflammation was reduced. So he found 2 things. First off, like us, no overall effect. That's the graph over on the left. He did not find an association with the inflammatory biomarker, but again, his numbers were lower to start with. But we know that early life adversity sets people up for inflammation in later life. So as a post hoc analysis, he looked at that. And if you look at the graph on the far right, these are people that got infliximab who did or did not have or gotten infliximab or placebo who did or did not have early life physical abuses kids. And what you can see is that in the population that had early life, there was a big, big benefit for infliximab. But look over in the middle graph, and there you can see at 12 weeks. That same signal that if you didn't have that particular behavioral biomarker, at the end of it, you did better with saltwater with placebo. So again, it's convergent data that is suggesting that there's something about baseline inflammation or other states that index inflammation that can be predictive of who is and who is not going to respond to blocking inflammation with a TNF antagonist. Next slide. And let me just say before I say this slide, I should have added one more slide that I didn't think of it until like 30 minutes before talking to you folks. So this finding that some people do better with a cytokine antagonist that blocks TNF and some people do better with saltwater is not unique to infliximab or to anti-inflammatory agents. In fact, there are large meta-analysis of regular old SSRI antidepressants like Prozac and Paxil, showing that if you look at individual patients, 1/4 of all depressed people who are put on antidepressants do much worse than if you'd given them a sugar pill, but here's the wrinkle. Unlike with TNF antagonists, we have no idea ahead of time with those 25% of people are that are going to be worse off because they got Prozac or Zoloft or Paxil. It's a crapshoot, whereas in the immune space, it increasingly looks like we can identify those people ahead of time and target them specifically with the treatment. Next -- oh, this is the next slide. I'm sorry, if you can go back. So after we did this study, Andy really -- Andy Miller really dug in. He's done just an amazing work showing that not only do depressed people who are healthy and have increased inflammation respond differently to cytokine antagonists, they also have different brain activity. So they have reduction in the pleasure center of their brain, an area called the Ventral Striatum compared to people that are just as depressed but don't have the increased inflammation. And they also have a disconnection between that pleasure center and what's called the ventromedial prefrontal cortex. It's very involved in assessing how you feel what you want to do with your life motivation. It fits with a symptom pattern because it also turns out that the other thing inflammation does is it makes people -- the word is anhedonia. They lose pleasure in life. They lose the motivation to do things that make them feel good. That's a depressive symptom, but it's especially represented in people with increased inflammation. So if I can have the last slide real quickly next. To summarize, inflammatory stimuli, in this case, interferon alpha, but others have been used promote depression in part through increased TNF signaling. So that's how inflammation does it. Groups of depressed individuals show increased TNF and other inflammatory biomarkers, but this results from a subgroup with elevated inflammation, non-specific TNF antagonist like we did with infliximab has no overall benefit in patients with unipolar or bipolar depression, but shows a signal in the subgroup of patients with elevated inflammation or early life adversity, which is associated with increased inflammation. Medically healthy patients with major depressive disorder and increased inflammation show unique changes in brain function and connectivity and tend to demonstrate increased anhedonia. So improved more specific TNF antagonists may represent novel precision medicine-based treatments for the subgroup of depressed patients with elevated inflammation. This love for precision medicine in the psychiatry has been the Holy Grail and again, it really looks like that these immune molecules may be our first targets for that kind of approach. So with that, I'll stop. CJ, turn it back to you.

Thanks, Chuck. And thanks, John. And just wonderful presentations. I appreciate both of you being here today. And as you've heard from Dr. Schneider and Raison, there is a desperate need for effective treatments for treatment resistant depression and there's considerable mechanistic evidence for targeting TNF. And this trial is the accumulation of more than a decade of research by Dr. Andy Miller and Jennifer Felger at Emory University, who, as Chuck mentioned, are coauthors on the original infliximab study. And as Chuck also mentioned, doctors Miller and Felger's research has really identified biomarkers to select patients that are not only most likely to respond to anti-TNF treatment but also biomarkers of treatment response. And this really was the basis of the grant that was submitted to the National Institute of Health. So the study is a Phase II placebo-controlled blinded study of XPro1595 in patients with treatment resistant depression and biomarkers of inflammation. This 6-week study will enroll 90 patients at 2 sites, Emory University and the University of Alabama, Birmingham, with site PIs, doctors Miller and Felger at Emory; and Dr. Richard Shelton at UAB, who is another expert in inflammation and well recognized scientist. To be eligible for the study, patients must meet the criteria for treatment resistant depression. In this case, it's failed 2 courses of antidepressive treatment and have biomarkers of inflammation defined as C-reactive protein greater than 3 milligrams per liter plus the presence of anhedonia, a symptom of depression that is sensitive to inflammation and Chuck just described a few moments ago. The primary goal of the study is to improve functional connectivity. So this is the connections that are lost between the striatum and the prefrontal cortex within the reward circuitry and to reduce biomarkers of inflammation. Clinical effectiveness will also be assessed as secondary and other measures, and the endpoints will be measured at baseline 2 and 6 weeks. Next slide, please. So while CRP has been used to select patients in the recent past, this really is the first study to our knowledge that combines a biological and behavioral biomarker shown to be sensitive to inflammation to select patients. Another novel element in the study is that we are assessing biological changes in the CNS using noninvasive methods. In the past, this had to be done with cerebrospinal fluid. We have previously shown in our Alzheimer's program that changes in neuroinflammation as measured by MRI, is sensitive to XPro1595. This study takes this one step further and will also measure biological changes that occur downstream of inflammation in the functional connectivity. So in particular, we'll assess whether XPro1595 can restore the functional connectivity between 2 areas of the brain that should serve motivation and reward and determine the extent to which early changes in these biomarkers can predict clinical effectiveness as determined by traditional measures. So with that, I'd like to thank you for your attention. And we will now move to the Q&A session.

Great. Thank you, everybody. And Dr. Raison, I've got 2 questions for you. The question was how many of the 60 patients had high CRP? And what was the p-value for that subset? This is the infliximab versus placebo? And then the same question, but for the Canadian subset, kind of the number in the p-value. Do you happen to know that by chance?

I don't know the p-value, for which I apologize. I'm getting older. Details don't stay with my brain the way they did before. The -- so there's elevated inflammation and there's elevated inflammation, and this is worth a comment. So generally, like healthy -- let's just take CRP. Generally healthy CRP is thought to be below 1. When we started in this work, 3 was felt to be sort of the upper limit of normal, if you're not -- don't have cancer or you're not 6, something like that. The cutoff I showed you we did by 1/3 sort of totals and that value was 5. That was the value at which the infliximab began to beat the placebo. That was 30% of this population. So a not insignificant number. But what I didn't show you is that if you plotted each person's response against CRP, there was no dividing line. It would -- it just went like this. It just went straight up. I mean it was like perfectly on the line. It was the most amazing thing. So the lower your CRP, the better you did with placebo, the higher you did the better you did with infliximab. Just as a comment, this is not just a cytokine antagonist blocker phenomenon. We've published some very, very large databases, showing that if you look at, in this case, say, an atypical antipsychotic, which more of a regular antidepressant for bipolar disorder, CRP totally predicts who will respond and who won't. Higher CRP, you get a response. Lower CRP, nothing. It's been shown in antidepressants. It's even been showing the things like omega-3 fatty acids. So it really does look like something that's real. So in Rogers Study, I don't know. And I should know, but I don't. But I know their levels were lower. And I know that he originally was going to have his cutoff. He was trying to recruit people with a CRP of 3 and he dropped it and dropped it and dropped it and eventually he had a lower concentration. We generally say that the rates of people that are in this elevated subgroup, if you take 3, for instance, as the cutoff, which is reasonable for a lot of these things, depending on the demographics of the place, it's 30% to 40%, 45%. It's a reasonable percentage of depressed people.

Thanks, Chuck. Well, another question here for you, Chuck, and this really goes back to the slide of sickness behaviors. Can you talk about the similarities of Alzheimer's and treatment resistant depression as it relates to sickness behaviors and how one might consider sickness behaviors as behavioral biomarkers of underlying inflammation that maybe transgress across all these different disease states. Is that something that seems reasonable to you?

Yes. Yes. Well, okay. So there's some interesting -- yes. So it's clear that inflammation plays a major role in Alzheimer's. And it's clear the people that have depression earlier in life are a greater risk of developing Alzheimer's later in life, unfortunately, for those of us that have had a bout or 2. But they are different. Depression has its onset of action early in life. Alzheimer's has late in life. Alzheimer's is a wear down condition. It really probably is mostly a modern problem, a problem of just a sort of chronic unrestrained inflammation that so bedevils the modern world, whereas depression, the inflammation seems to be much more related probably to these older evolutionary drives. But to this question of phenotypic or behavioral biomarkers, this is a really important point because, as I understand from Andy, some of the -- one of the interesting things about the study you all are doing is that it's not just a biomarker that you're looking at, it's also this measure of anhedonia. And you can do this thought experiment yourself. Think about the last time you really had the flu, and I bet you that you -- that this symptom of anhedonia -- when you're really sick, even if you don't feel depressed, you don't want to do stuff, right? I mean there's just a loss of interest, all you want to do is lay there. And it's not just you're tired, there's an evolved mandate not to go chasing the pretty girl down the hall or some sort of big thing at work or sports. No, you need all your energy to just lay still and fight the infection. So the anhedonia in the context of sickness is an adaptive evolved response. It may or may not be have been across evolutionary time with depression, but the fact that you see increased anhedonia in people that are depressed with elevated inflammation speaks to it being a transdiagnostic biomarker that you see associated with inflammation. And of course, apathy is just a primary early symptom of Alzheimer's. Depression is also, but apathy is especially striking. And it goes along with the fact that Alzheimer's, especially early in the disorder, is an inflammatory state. So there are those connections.

Great. Thank you. So John, let me ask you a question about how the market would view segmenting patients for TRD with biomarkers? It's not -- there aren't any products on the market right now that actually do that use biomarkers. What are your thoughts on how it would be viewed from both the scientific community and from the payers' point of view?

Yes, CJ, that's a good question. And we've seen -- this is really kind of still in the grand scheme of things, relatively new thing. And that's companion diagnostics. And we see it most often now in oncology. And what we do see is that payers are embracing companion diagnostics in oncology, but really only ones at work. And by work, I mean, as I -- in my last slide, the ones that I can identify the population in which the payer is going to get the most bang for the buck. So that's the population of sort of high responders or at least moderate to high responders. What payers don't want to pay for is a lot of nonresponse. And actually, that's what they're paying for now. They're paying a lot of money, maybe not on a per patient per month basis because a lot of these [indiscernible] are generic. But there's still -- it adds up very quickly and certainly, slightly increasing year-over-year prevalence. Payers are paying more and more out of pocket for treatments that essentially aren't doing anything, aren't working. So I think there'd be a lot of interest among payers and biomarkers in this area. As Chuck alluded to before, it's sort of the holy grail. I think this is an area that payers would have a lot of interest. Yes.

Great. And Chuck, we've got a question here about the importance of a drug getting across the blood-brain barrier to treat depression. What are your thoughts on that as being a necessary element for success?