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

Good morning, everyone. I'm David Moss, CEO of INmune Bio. Thank you for joining us today. INmune Bio is a clinical stage biotechnology company developing therapies that target neuroinflammation in neurodegenerative disease. Our lead program, XPro1595 is a first-in-class selective soluble TNF inhibitor. It works by blocking the form of TNF that drives pathology while preserving the form that supports normal immune function. That distinction is central to everything you'll hear today. The objective of today's webinar is straightforward to demonstrate how clinical results of our Phase II MINDFuL trial directly forge the blueprint for our registration program. Following a very productive end of Phase II meeting with the FDA, I am very pleased to report that we reached alignment on the core elements of our Phase III registration program. Today, we'll walk you through the data-driven rationale and the optimized design that will carry XPro through this final stage of clinical derisking. The MINDFuL trial was strategic lean proof-of-concept designed to solve for 2 critical variables, biologic signal and patient selection. The trial was a first of its kind, a short, small enriched population study in Alzheimer's disease. It was designed to answer 2 specific questions. Does XPro show biologic activity in patients with AD and biomarkers of inflammation? And can we identify the right patient population for a registration trial? The answer to both was yes, providing us with a validated precision medicine road map for a Phase III registration program. The data from MINDFuL directly informed every element of the registration program you'll hear about today, the population, the endpoints, the trial duration and the design. It's the foundation of everything that follows. With that behind us, now let me introduce our speakers. Dr. Michael Woodward is an Associate Professor and Director of the Memory Clinic at Austin Health in Melbourne, Australia. He's a globally recognized expert in Alzheimer's disease clinical development and served as a site principal investigator in the MINDFuL trial. Dr. Woodward will walk you through the Phase II data. Many of you know Dr. CJ Barnum, who is our Vice President of Neuroscience and has led the AD program since its inception. CJ and his team designed the MINDFuL trial, led the end of Phase II interactions with the FDA and developed the registration program you'll hear about today. CJ will walk you through how the MINDFuL results shape the trial design and what the FDA aligned on. Also, we're delighted to have Dr. Sharon Cohen, who is the Medical Director of the Toronto Memory Program in Canada. She's one of the most experienced AD clinical trialists in the world and was also a site PI on MINDFuL. Dr. Cohen will join us live during the Q&A to provide her independent perspective on the trial design, the endpoints and the clinical meaningfulness of our approach. Due to the time zone constraints, the presentations have been prerecorded, but Dr. Cohen and CJ and myself will join us live for Q&A. With that, let me hand the webinar over to Dr. Woodward. Dr. Woodward?

Thank you, David, and thank you for the introduction. I'm excited to be a part of this webinar. I was a site Principal Investigator during the Phase Ib as well as during the Phase II trial. To get going, I'll summarize and share the data from MINDFuL, the global Phase II proof-of-concept clinical trial, assessing the treatment of XPro1595 in early Alzheimer's disease. The top line data was shared last July. INmune Bio set out to test XPro in Alzheimer's and specifically in a population that match the biology of the drug. To this end, they initially recruited participants positive for amyloid to prove they had amyloid that Alzheimer's, but with at least 2 biomarkers of inflammation, which is the sweet spot for the mechanism of this medication. However, it became too hard to initially recruit in the time lines available. So pragmatically, it led to a dilution of the inclusion criteria. And this study had 200 participants in the modified intent-to-treat population, but 100 in the targeted enriched population that better matched or completely matched the original entry criteria. We will follow this targeted population, those that had at least 2 markers of inflammation across this webinar. We also call it the ADI for the Alzheimer's disease with inflammation group. And this is the term used in the manuscript, which is on medRxIV and includes participants with both biologically defined Alzheimer's, i.e., amyloid positive scan and 2 or more biomarkers of inflammation. Now we set statistically meaningfulness at P of 0.1, which is quite appropriate for such a small population. Due to the loss of nearly half of the sample size when analyzing this ADI Alzheimer's disease inflammation population, statistical p-values were less likely to be reached. Instead, INmune Bio chose to assess the meaningfulness of the data by means of an effect size and specifically the Cohen's d effect size, an absolute effect of about 0.2 or higher was said as meaningful in this short study. And I might say by comparison, the drugs will be used already for treating Alzheimer's such as donepezil, have effect sizes of about 0.2 to 0.3. So it's a reasonable choice of effect size. The next slide here shows the population and the subgroup, the ADI population on active drug compared to placebo drug. So there are 100 participants, 28 randomized to placebo and 72 to XPro treatment. And you can see that the general comparison of baseline characteristics between the placebo and the XPro-treated groups are pretty much the same, but we do want to highlight 2 characteristics on which there was a slight difference. The CDR global score, which is the clinical dementia rating global score at baseline was slightly worse. In other words, the XPro participants were slightly more affected by the disease with 28% having a score of 1 compared to only 14% in the placebo group who were more mildly affected. And this value of 1 basically means that they have significant memory problems and likely some changes in other areas. Also, the XPro participants have a slightly higher average number of biomarkers of inflammation. But this implies that the XPro group may have had slightly more aggressive disease and particularly disease progression at baseline, although by having more markers of inflammation, we also have better opportunity to show an effect of the drug. Anyway, basically, the slide here shows that the XPro group overall had probably slightly more advanced or progressive disease than the placebo group at baseline. Now on this next slide, you can see the design of the study. We have randomization of 2:1, and there's a relatively short treatment duration for this. It's only 6 months. Many of the Alzheimer's disease-modifying trials that we're doing at the moment go for 18 months. But remember, this is a proof-of-concept trial. The primary endpoint is the early and mild cognitive composite or the EMACC, and it measures cognition in a number of ways. This is a proof-of-concept study in which we allow ourselves to learn by measuring across modalities for a more thorough picture of the drug and its effect in Alzheimer's disease. Now on this next slide, you'll see the first and the primary endpoint, the EMACC, the dotted line being placebo and the blue line being the treatment group. You'll see that at baseline, there was a suggestion that the placebo group had worsened and the treatment group had actually improved, and there was a difference between the 2. The p-value was above the 0.1 that had been set and the Cohen's effect size was 0.27. I think, however, it's important to see that this is showing the directions that we would like to see because of the treatment with this medication or this investigational product. Now normally, over a 6-month period, we'd expect to see the placebo group decline. We did see that. But we'd also expect to see the treatment -- I mean, a nontreated group maybe say decline less. But to actually see a slight improvement, I think, is quite remarkable. In the next slide, we can have a look at a couple of the other endpoints. This is the clinical dementia rating sum of boxes. And again, you'll see a slightly worse rate of decline, the dotted line in the placebo group than in the investigational product group. This is not unexpected. We don't expect the drug to usually cause improvement. That's why the last results were so remarkable, I think. But we do see a difference trending towards improved or less decline, if you like, with the inflammatory subset of the Alzheimer's group. Now if we actually break it up into dose compliance, by which we mean people who have had at least 21 milligrams per kilogram out of the total 23 milligrams per kilogram over the trial group -- over the trial duration, we see a bigger difference between the treatment and the placebo group. So taking the drug gives you a greater effect, which is, of course, what we would expect. On the next slide, we're looking at another endpoint. This is the neuropsychiatric inventory. We see little change, which is not unusual in these sorts of trials in the treatment group, but a worsening, in other words, more neuropsychiatric symptoms in the placebo group. Generally, what we're trying to do with treatment is to stop emergence of symptoms, and that's what we see in the blue line group, that there was no change. In other words, no new symptoms emerged or no current symptoms got worse. But in the treatment group -- sorry, in the placebo group, we see that there was a deterioration, either new symptoms occurred or existing symptoms worsened. And again, P is 0.2 and the Cohen's effect size about 0.23 or in the dose compliant 0.27. On the next slide, we see the first biomarker change. This is phospho-tau in the plasma. Phospho-tau217 is regarded as a very good indicator of brain amyloid and the neurodegeneration that occurs in Alzheimer's. And again, we see a higher rise, that's a bad thing, a higher rise in the placebo group than we see in the blue line treatment group with a slightly greater difference in those who are dose compliant. Again, p-values are shown on this slide, Cohen's effect size in the dose-compliant group, 0.26, which is above the 0.2 that it was set at. GFAP, which is glial fibrillary acidic protein, is a marker of the activity of the inflammatory cells around the amyloid plaque. And the higher the level, the greater the level of inflammation. And we see a lesser rise in the XPro group, particularly in the treatment-compliant group than in the placebo group, which rose higher, indicating that the XPro group seem to be, to some degree, modulating that inflammation, which is exactly the postulated mechanism of action. In the next slide, we've summarized the results across all these endpoints -- and you'll see very reassuringly in terms of hypothesis generating and in terms of going to the next stage of investigation that most of these endpoints favored XPro. There's only one that did not. But I would say that if we look at these and particularly if we look at the effect size, remember, we said 0.2, many of these were around 0.2 or higher. I think we can see an overall palette of the effectiveness of this drug in the inflammatory subset of Alzheimer's disease and not shown here, but probably particularly so in those who are most dose compliant. So I think this is very, very reassuring, and I think it's a good indication that we have a drug that may show effect in Phase III study, but I'll let CJ talk about that. One of the concerns with new potentially disease-modifying therapies, particularly the new amyloid targeting therapies is ARIA. ARIA stands for amyloid-related imaging abnormalities. And there's 2 sorts, ARIA-E, the E standing for edema and ARIA-H, the H standing for hemorrhages, particularly microhemorrhages. These are actually causing a significant number of people to have to withdraw from the current amyloid targeting therapies that are on the market and certainly have to be carefully and regularly monitored with MRIs and other safety assessments. It would be great if this drug can be shown to have no risk of ARIA. And indeed, we saw that both in the placebo group and in the treatment group, there were no examples of -- or no cases of ARIA-E or ARIA-H. And that was seen over the whole population, 206, not just the ADI population. But it's also important to know that these patients, both in the placebo and in the treatment with the investigational product group had risk factors for ARIA. Some of the risk factors that we recognize are preexisting cerebral microbleeds, and you'll see that nearly 35% of both groups had these at baseline. The use of antithrombotic agents, these agents were not excluded unlike the protocols for many of the new amyloid targeting therapies where being on particularly an oral anticoagulant is an exclusion from the study. This study allowed you to be on anticoagulants and antithrombotics, and you'll see that about 25% to 28% were in this particular study. Also, the ApoE4 gene is seen as a risk factor, particularly for ARIA-E. And in this group, we had 55% with 1 ApoE4 gene, and we had 12% to 13% with 1 -- with 2 copies of the ApoE4 gene, that's E4 homozygous. These are the ones who are particularly at risk of ARIA-E. And again, despite this risk profile, we did not see ARIA, either ARIA-E or ARIA-H in this study. And I'd like to hand you over to CJ, who I've known for over 5 years, and I cannot tell you the passion, the knowledge and the wisdom of CJ in seeing that the tumor necrosis factor angle is very important for potential treatments of Alzheimer's disease and not being blinked by the amyloid is bad, let's get rid of amyloid approach that so many other drugs and companies have taken. So CJ, you're up.

Thank you, Michael. We very much appreciate you taking the time to lend your considerable expertise and experience to this webinar. My name is CJ Barnum, and I'm Vice President of Neuroscience at INmune Bio, and I've had the privilege of leading XPro's clinical development in Alzheimer's disease. You just heard what the drug did in Phase II. The key takeaway, consistency, cognition, neuropsychiatric symptoms, plasma biomarkers, imaging, patient-reported outcomes. Nearly every assessed domain favored XPro in the ADI population. That totality of evidence is what the FDA saw when they reviewed our data. So where do we go from here? Today, I will show you the road map, walk you through why the FDA agreed with our approach and what gives us confidence it will work. We recently completed an end of Phase II meeting with the FDA. That's a big milestone. We presented our full scientific and clinical rationale to the agency and had a structured back and forth about the path forward. Before I tell you what they said, let me show you the design we presented to them. On the left is patient selection. XPro is designed to treat the subset of Alzheimer's patients whose disease is driven by TNF-mediated inflammation. These are patients who carry at least 2 of 4 inflammatory biomarkers, C-reactive protein, sedimentation rate, hemoglobin A1c and at least one ApoE4 allele. These biomarkers were chosen because they're mechanistically connected to the biology XPro targets. The study design has 2 stages that allow us to replicate the findings of MINDFuL in a Phase IIb and then seamlessly roll into a Phase III registration study if we hit our marks. This approach balances scientific rigor with speed, confirming the signal before scaling to registration. The Phase IIb is a 9-month confirmation stage that will enroll around 300 ADI patients. The co-primary endpoints are EMACC and plasma p-tau217. In MINDFuL, we saw an effect size of 0.27 on EMACC at 6 months and an initial signal on p-tau217, suggesting XPro is impacting the underlying disease process. The additional 3 months and larger sample size gives us more time for placebo decline and the statistical power to detect separation. Advancement to Phase III will require 1 of these 2 co-primaries to succeed. The trial is statistically designed so that either one succeeding is a valid win. The decision gate is a derisking milestone. You get a powered go/no-go signal before the Phase III capital commitment. The FDA also recommended we include about 20% non-enriched patients. These are patients without the inflammatory biomarker profile as an exploratory arm. If XPro shows a signal in that group, the addressable market expands dramatically. If there's no signal, those patients don't follow us into Phase III, keeping enrollment focused and cost efficient. That's upside without obligation, focus where the drug works and don't spend where it doesn't. Phase III is a registration trial. We'll enroll approximately 1,000 enriched ADI patients with the CDR Sum of Boxes as the primary outcome measure at 18 months. That gives us the statistical power we need for regulatory approval. We're targeting a 2027 start, and David will walk you through the funding strategy. The FDA validated our approach in 4 important ways. First, they endorsed our biomarker-based enrichment strategy. They were comfortable with the mechanistic link between TNF and each biomarker, the assays, and this was the one I expected the most pushback on using a combination of biomarkers rather than a single biomarker to define our patient population. Second, they endorsed the adaptive Phase IIb/III design, including the decision gate with EMACC and p-tau 217 as the go/no-go endpoints. Third, they agreed on CDR Sum of Boxes as the sole Phase III primary endpoint. It's the registration standard for Alzheimer's because it captures both cognition and function in a single measure. And fourth, they recommended including a non-enriched cohort in Phase IIb. This serves as a built-in validation of our enrichment strategy. But before I move on, one thing. Just last week, the FDA leadership published in the New England Journal of Medicine that a single, well-controlled trial backed by mechanistic coherence and biomarker data is now the default standard for approval. That means a single well-designed Phase III trial with the kind of convergent evidence we already have could be sufficient for registration. So let me address the question we get asked most often. If the CDR Sum of Boxes showed no separation in Phase II, why are we confident it will work in the Phase III study? Two reasons and both come down to how the CDR Sum of Boxes works and how long it takes to show change. Let me explain. Simply speaking, cognition is the leading indicator and function is the lagging indicator. Cognitive decline precedes and predicts functional decline. In the kind of early-stage patients we enrolled in MINDFuL, functional deficits are barely detectable if they're present at all. More importantly, functional deficits require more time to become measurable because deficits emerge slowly. Cognitive deficits, on the other hand, show up early and as a result, can be detected with sensitive tools like EMACC. The data bear this out. The correlation between cognition and function in early disease where functional deficits haven't emerged is low, approximately 0.41. However, as functional deficits appear, this correlation strengthens considerably, climbing to 0.65 at 18 months. At this point, the CDR Sum of Boxes is able to catch what EMACC has been detecting all along. In clinical trials, cognitive treatment effects consistently propagate into detectable slowing of functional decline at 18 months. Let me make this sensitivity difference concrete. Think of EMACC as a stress test for the brain. It measures subtle cognitive changes. For example, your ability to recall a word list or how fast you can process information. Take word recall. You read a patient 15 words and they recall as many as they can. And then you repeat this process across several trials. In the early stages of disease, the patient might recall fewer words or take longer to recall those words, but the patient can still manage life independently. This is what EMACC captures. The CDR Sum of Boxes is asking a fundamentally different question. It uses broad scoring categories like none, slight, mild and relies on a caregiver reporting, someone who may or may not be attuned to the patient's day-to-day cognitive changes. That subjectivity, combined with broad scoring categories means a patient has to decline substantially in day-to-day function before the score moves. EMACC detects subtle cognitive changes. CDR Sum of Boxes waits for the consequences. But EMACC captures at 6 months, the CDR Sum of Boxes captures at 18. What you're looking at here is a conceptual framework, not derived from trial data, but it shows the window where each instrument can reliably detect a treatment effect. The x-axis depicts the stage of disease and the y-axis reflects the ability to detect a treatment difference. The purple horizontal band is the detection threshold, the point where a clinical instrument can reliably measure change. The blue curve is EMACC. Because it is a sensitive performance-based measure, it crosses that detection threshold early in the disease process. At 6 months, it is sensitive enough to pick up the treatment signal as it did in MINDFuL. At 9 months in Phase IIb, with more time and a bigger sample, the likelihood of detection increases. The magenta curve represents the CDR sum of boxes. It uses broad scoring categories. So a longer change in day-to-day function is needed to move from one score to the next, which means it crosses the threshold later. 9 months may be a bit too early still, which is exactly why the CDR Sum of Boxes is not a Phase IIb decision-making endpoint. By 18 months, however, untreated patients will have shown measurable decline on the CDR Sum of Boxes, allowing us to detect treatment differences. That's when it becomes the right instrument. Same patients, same drug, just different windows on the same underlying biology. The EMACC shows early change that with time becomes measurable by CDR Sum of Boxes. We have the leading indicator, now we need the time. Let me bring this all together. We built this program on a simple premise that Alzheimer's patients with TNF-driven inflammation are a definable, treatable population. It's not a retrospective discovery. It's a hypothesis we've been testing from day 1, and that's what the FDA validated in our end of Phase II meeting when they aligned on our enrichment strategy, our endpoints and our trial design. The Phase II data gave us an early cognitive signal on EMACC at 6 months. The literature tells us that signal will translate into functional outcomes at 18 months. The adaptive design means we'll confirm it at 9 months before we scale to the full 1,000-patient registration trial. Every step is sequenced to answer the next question before committing the next dollar. This Phase III is built on a scientific foundation. The right drug, the right patients, the right measure at the right time to generate a definitive answer efficiently. I'll now hand it over to David to walk through the path to execution. I'm looking forward to taking your questions at the Q&A. David?

Thank you, CJ. Before we open the floor to questions, let me address the question I know many of you have on your mind. How does this program get funded to move forward? The Phase IIb/III design is deliberately staged. The Phase IIb portion, roughly 300 patients and 9 months of treatment is where we will confirm the enrichment population's responsiveness. The data at 9 months does not meet our threshold and at least 1 of 2 current primary endpoints, we will stop. That built-in decision gate limits capital exposure and makes this an attractive structure for partners. To that end, we're in the final stages of engaging an advisory bank to run a formal global partnership process. This package we bring Phase II clinical data, FDA alignment on registration design, a well-characterized patient population and a first-in-class mechanism with no signs of ARIA is, we believe, compelling for a mid- to large pharma partner with interest in neuroinflammation or Alzheimer's disease. I think everybody on the call knows this is a huge unmet need with a very large market. In parallel, we continue to advance CORDStrom, which provides both potential revenue and a priority review voucher. And these catalysts -- as these catalysts develop, our position in the capital markets should strengthen. On the operational side, we're already moving. Protocol development is underway, and we've begun planning for CMC scale-up and site feasibility assessments. We are building this program so that when the funding is in place, we're ready to go. It's now time to move to Q&A. Let me look for questions, and I'll come right back.

All right. Thank you, everybody, and CJ and Sharon for joining us. I have a handful of questions, but I'm going to start with my question first, if you don't mind, to you, Sharon. I was very fortunate enough to see you present our MINDFuL Phase II data at AAIC. Thank you so much for doing that in August. And obviously, we had a good-sized room there. And I'm wondering if you can share any of the responses that you received from your presentation.

Yes. Thank you, Dave. It was a pleasure to present that data, and it was a pleasure to receive responses from colleagues who had a lot of questions and a lot of interest. They didn't view this as a failed trial because we didn't meet our primary at 6 months. They view this very much as how do we move forward because on so many endpoints, as Dr. Woodward showed, we favor XPro in the enriched population. And I think that in a proof-of-concept trial, you want to figure out who's the best group of patients to study. One comment that was repeatedly made to me is that people were so impressed that at 6 months, we could see so many endpoints show a positive effect size. And that's not what we're used to with disease modification in Alzheimer's. We usually have longer Phase II studies and don't expect to see things at 6 months. So I think that was also a takeaway.

No, I appreciate that. Thank you. It was a large room with a lot of people there. It was a great experience. One other question. You've been involved with multiple companies developing many different therapeutics in AD and have a good grasp of the AD development field given your experience. What do you believe is INmune Bio and/or XPro's greatest differentiator and strength?

Yes, that's a great question. And I have been involved in clinical trials for 30 years, Phase I to Phase III in Alzheimer's research. And as we move more and more in our field towards precision medicine, really defining the patient population clinically and biologically, I think the XPro program really takes this to the next level, where we are enrolling based on certain biomarkers match to the drug's potential and looking at this enriched population from the standpoint of cognition, function, patient-reported outcomes and biomarkers. That is definitely the way to go. With the anti-amyloid treatment approaches where we've had some success, it's taken us a long time with a lot of failures to get where we got, and we needed biomarkers. They were essential to the success of those programs. And I think that they will also lead to success here. There's a great appetite for targeting other pathologic abnormalities in Alzheimer's beyond amyloid. And inflammation is such an important target. And not only could it be a stand-alone way of treating Alzheimer's, it could augment the effect of anti-amyloid therapies and furthermore, reduce the risk of ARIA for anti-amyloid therapies by modulating inflammation in the brain. So in so many ways, there is a unique aspect to XPro. And yes, I'll stop there.

No, I appreciate that. And I think this next question is it kind of dovetails into what you just said about neuroinflammation and the disease, and I'll present this one, I think, to CJ and well, maybe both of you. Treating neuroinflammation is important in neurodegenerative disease and specifically Alzheimer's. Number one, what makes XPro different -- and then the second part of that is the ADI or this inflammation enriched population, how does it improve the chances of success in the new trial? In other words, this inflammation enriched population. I think that's probably best for CJ to start.

Yes. So the first part of that question again, David?

About the uniqueness of XPro in targeting neuroinflammation.

Yes. So I think this is where I get particularly excited about this drug and why I've been working with it for nearly 20 years now is because it does something very different, right? The immune system, really, in my mind, this changes the way we view the immune system and how to target and treat it. Because what we're traditionally doing with targeting inflammation is we are suppressing it. I mean that's how the therapies work, and they're very successful when you have diseases where the immune system is extremely strong. But neurodegeneration is a little bit different. Neurodegenerative disease is a little bit different because it appears to be that the immune system just becomes dysfunctional. You get this sort of immune exhaustion that occurs, and that is a fundamentally different thing. So it's not just the immune system is overactive, which it is, but it's also not doing the homeostatic stuff that it needs to do. And I think we fundamentally underappreciate how important the immune cells are to the brain. I always use this example of neurons being like infants, right? Infants, they can't feed themselves. They can't bathe themselves. They can't socialize themselves, and they require parents to do that or else they die and they can't thrive. And that's really what the immune cells are. The immune cells provide all those parental needs to the neurons. And I just don't think we appreciate that well enough. So from the perspective of developing therapies that target an immune system that's not functioning properly, you don't want to suppress it because if you suppress it, yes, you reduce some of that inflammation that's driving some of the disease, but you don't get the benefits of repair, restoration and that sort of thing. And that, in my opinion, is the key difference. We're able to -- XPro is able to normalize the function of the immune system in a way that not only stops it, but allows it to repair and rebuild and restore the things that we've lost. So I think that's what is sort of the key piece or the differentiator with XPro. And I forgot the second question, too.

The second part of the question was the inflammation-rich population, how it improves the chances of success in the trial.

Well, I think the simple explanation is you just need to look at cancer, right? I mean cancer started to become extremely successful and we started to match the mechanism of action with the biology of the patient, right? So we don't talk about a therapy for cancer. We talk about a therapy for specific types of cancers matched by biology. Even within certain cancers like breast cancer, you're matching it within biology, HER2-positive, right? So this is where the success ultimately comes is matching the pathology of the patient with the mechanism of the drug. And to be fair, the reason it's taken a little bit longer in the neurodegenerative space is because it can't really do a biopsy of the brain, right? So we don't have the same tools that we have with peripheral cancers where we can biopsy and really look at the mechanisms and tie the biology. It just so happens that inflammation is one of the things that we can measure and we can assess because we know a lot about it. We know how inflammation between the periphery and the central nervous system reflect each other. And I think that's a real positive and allows us to be somewhat early in matching pathology with patients because of that.

And maybe I could just add one point. I agree with everything that CJ said. But when you have an enriched population with more inflammation in the brain, the untreated group, the placebo group is more likely to decline and you are much more likely to see a separation between treated and untreated.

Yes. And then one last question that I'm going to tag on is, why did you see a bigger effect in the neuropsychiatric patient -- the neuropsychiatric inventory or the symptoms associated with XPro. Is that because neuroinflammation is a big driver of neuropsychiatric symptoms?

So you want me to take this, Sharon?

Sure. I might add on after.

So what's interesting is the literature with inflammation and neuropsychiatric disease is actually longer and has more history than even with neurodegenerative disease. And we know a lot about how inflammation and neuropsychiatric disease sort of go hand in hand. So that's not particularly surprising. The other thing is from a neuropsychiatric disease perspective versus neurodegeneration, we're typically talking about cells that are losing connections, right, as opposed to losing cells in neurodegenerative disease. So if you restore the immune system where they can repair the biology that currently exists, you should be able to change those neuropsychiatric diseases or those symptoms pretty early. Now that's not entirely true because sometimes the neuropsychiatric symptoms are resolved of the degeneration that occurs over time. But we know in depression studies, for example, those changes occur quite rapidly when you give, for example, TNF inhibitors to patients with neuropsychiatric disease, you can see changes very quickly because you're able to restore the balance pretty quickly, if that makes sense.

That's so interesting that neuroinflammation has potentially a direct impact on behavior and neuropsychiatric symptoms. And I think there's another possible explanation that could go hand-in-hand. If XPro is reducing cognitive decline, then as a downstream effect, you would have less frustration, less agitation -- sorry, just the way cognition drives function, cognition drives behavior as well. So I think both explanations fit hand in hand.

That's great. Thank you. I have a question here from Tony. He says, "Hello, David, with the Phase II trial being successful, why do you think it's not reflected in your share price?" That's a really frustrating question that we deal with. I think twofold. I'm going to answer that twofold. Number one is most people think the trial was not successful. They don't realize that in a Phase II study, if we would have had the right population in there, all 200 patients or close to 200, it probably would have been a great success. We're amongst the first to ever do an enriched neuroinflammation trial. And when you're the first, there's just certain things that you don't know. And really, this trial was an R&D experiment and it defines the patient population for a successful trial. Second thing I'm going to say is that when you're the first doing something novel and there is nothing to look at a proxy or an example of, for example, there were many anti-amyloid trials that were run that failed and they refined, they refined, they refined and they got better and better and better, and they finally got it approved. We don't have that luxury in what we were doing. And so we're really writing the playbook for this trial, and we're learning along the way to make this trial successful. And in biotech development, my experience has been that the companies that are doing, let's say, a cancer drug that follows the pathway of many other successful cancer drugs that have been approved, it's very easy for investors to jump on board. But when they're going after something for the first time, think of like a CAR-T, for example, the initial CAR-T companies until they had success -- really good data, it took a while for them to get valued really appropriately. And then once they had the data and got it approved, they were wildly valued. And we had hundreds of CAR-T companies after that instead of just a few. I kind of feel like we're in that avenue where we're pioneering an approach. We're writing the playbook as we go. We're doing a very novel approach in Alzheimer's disease, which can expand into neuroinflammation, and we're paying the price. Over time, we'll figure out a way to get there. I think we've come up with a very sophisticated and rational strategy to get there. It's going to take us longer than we had hoped, but I think it's a prudent way to go. Okay. Next question. I'm going to send this one to you, Sharon. What would a potential future approval of a drug like XPro mean for people living with Alzheimer's disease and their families?

Well, this would be huge. This would offer another choice in therapy to slow down disease, potentially stabilize symptoms, cognition, function, neuropsychiatric symptoms and get at an important underlying pathologic mechanism without, as CJ said, without suppressing the immune system. We don't want to damage the ability of the immune system to do its job to provide trophic factors and everything else. We want to shut off the pro-inflammatory aspect. So for patients, for families, this would be a welcome addition, whether it's taken alone or in combination with anti-amyloid therapies. And the safety profile is really important here and the mode of administration. People can take the drug as a subcutaneous injection once a week at home. They're not tied to infusion centers. They can travel. We're talking about mild patients who have busy lives, some of them still in the workplace or busy traveling around the world, and they can self-administer the drug. And they don't have to be tied to MRI facilities for ARIA monitoring. There is no ARIA. So again, this would be a very welcome addition to the treatment armamentarium for patients. And for clinicians, the ease of use would be also welcome.

Yes. And just tagging on to the question. We have 2 platforms, one that's in a pediatric and then obviously, this one is to treat Alzheimer's patients. And when you see the families, my father suffered from Alzheimer's disease and you see the patients, you get very motivated to try and do something for them. And we've got 2 great platforms at this company. And I can tell you that everybody in the company is extremely motivated to figure out a way to bring these products to the patients and their families. We always like to say that you don't really treat the patient, you treat the family, and it's very, very true. Next question, CJ. The FDA end of Phase II meeting and alignment is a large milestone for XPro's development. What makes you excited for the next steps of XPro in view of this recent end of Phase II meeting with the FDA?

I mean there's a lot of things to like, but I think one of the things that was really surprising to me was the FDA got it. They understood it. And the conversation was so easy that was really exciting. And what it told me was that we have a partner in this. So sometimes people talk about the FDA as sort of butting heads and trying to figure out a way how to work with them and get them to understand what they're doing. I think they understand. They get it. They were they were very accommodating. They -- and so I think as we move forward, our ability to engage with them in a meaningful way is better than I would have expected. And I think I'm really excited for that because that potentially is a major roadblock. You can have a drug that works well and people just don't understand it, right, for whatever reason. And that regulatory hurdle is pretty big. So I think that -- being able to get past that is a huge milestone for us. And really, it's just a matter of let's run the study, let's get it done. And that really excites me.

Great. Thank you, CJ. Question here from Tim. Can you speak to the partnership path in previous discussions with pharma and their key issues, concerns, pushbacks? I'm not going to speak to what we have currently going on. I'll tell you that we recently just got the minutes from the FDA. It took us a while to go to get that. And now that we have that in hand, we have a real complete package, as CJ has outlined to you. We have a clear path on how EMACC at the 9-month -- EMACC and p-tau at the 9-month period drive the go/no-go decision to go to registration part of the program or not. It's not a huge costly expense for really, frankly, a multibillion-dollar opportunity treating millions of patients that are in need of additional therapies. We think the value proposition with the complete package is very attractive. And really, what we want to do now that we have those minutes in hand, which are just a few weeks old now, is do a very blanketed approach to the mid- to large-sized groups out there that would have an interest in neurology. And we do have some ongoing discussions, and we're going to continue those. We're sharing this information. It is not a quick process. Pharma by nature are very conservative, and it takes a lot of time to educate them just like we've had to educate the FDA and we have to educate the investor market. We also have to educate partners, especially since this is a new modality of an approach. And I'd say concerns or pushbacks, I don't think we've really had a lot of pushbacks. I mean it's also a timing issue, finding -- the partners have to be in a position where they're ready to do something. There's a lot of external factors where they may or may not be ready at the particular time. So timing is the issue. But we haven't had any real -- I mean, what would you say is any -- have we had any negative real pushback, CJ?

No, I don't -- I wouldn't characterize it as negative. I think you're right. I mean pharma -- the way pharma makes decisions is quite interesting if you get a peek behind the curtain. And it's not always clear why and how they decide things. But I think that to David's point, they were really waiting to see what the FDA said about the data and the path forward. I mean that's a huge decision-making point. Being able to come to them and say, look, here's what we discussed with the FDA, here, the minutes. They'll be able to see that there's alignment that there is a path to a commercial path for this, where I think if you're doing a completely different mechanism, which, to be perfectly honest, I don't think generally speaking, the scientific community understands inflammation. I think they know it's important, but I don't think they understand it. And so if you've got a new mechanism and you've got a new strategy, we're using biomarkers to enrich and we're using biomarkers in a different way that they are, they want to understand how does the regulatory agencies view this. Do you really have a program where there's a path to registration. And now I think once with this alignment, we'll be able to put this together, we'll be able to have discussions that I think will be meaningful. But to David's point, it does take time. I mean there's multiple -- these big companies have lots of different divisions and they sort of go back and forth. So we'll get there. But I think this is really -- I wouldn't call it a pushback. They just wanted to see how the regulatory agency was going to respond.

Yes. And I'll just add one last thing is that if we don't get a partner, or we don't like the terms of what a partnership look like. We're -- next year should have CORDStrom approved in 2, maybe 3 jurisdictions, U.K., Europe and the U.S. If we get it approved in the U.S., it comes with a priority review voucher, and we should be in a much better capital situation having a product approved. There's partnership potential there and obviously, revenue generation and potential PRV. That's money that at that point, we'll be able to turn around and complete the Phase IIb portion ourselves. So we're going to run this company prudently. We're going to -- our primary goal is to get XPro over the -- sorry, to get CORDStrom over the line first. That's where our growth is happening. That's where our resources are going. Meanwhile, in the background, we're getting XPro ready for the start of the Phase III program. We're doing everything we can with the limited resources we have. It's a wonderful program. It has a real potential meaning in patients' lives. It's a product that needs to see patients, and we're dedicated to figuring out a way. So I don't have any other questions. I'll give 1 minute for people to see if they're going to type anything. Is there anything, Sharon, that you want to say or CJ, you want to say before I -- if I don't get any more questions before I read the conclusion and sign off.

Maybe I could just comment for a moment on the unmet need. Yes, we have anti monoclonal antibodies. And that's great. And the landscape is evolving and many of us are adapting to patients being on these treatments. But they're not for everybody. In many jurisdictions, ApoE4 homozygous are excluded, people on anticoagulants are excluded. And I think having an alternative option for people who have this high unmet need is so important and tackling inflammation, I think, for all patients with Alzheimer's is important. But if you enrich for this and you don't have the exclusions that we have for monoclonal antibodies either on the market or in trials, you will recruit well for your Phase IIb/III study. I think that I, as an investigator at a clinical trial site would have no problem enrolling patients in this upcoming study. I look forward to that.

Can I ask a follow-up question to that, Sharon, because I'm very interested in your thought as a site PI. If -- or as the anti-amyloid therapies become more standard of care and people are doing clinical trials, my take is there's real -- I don't want to say unrest, but reservation about how do we incorporate new therapies where anti-amyloids are standard of care, right? It changes -- somewhat changes the calculus of who you enroll and how you enroll your studies. And from a regulatory safety perspective, are these things going to play well together? How do you -- without putting words in your mouth, how do you see XPro in that regard as it relates to, would you have any reservations of treating someone with XPro if they were on an anti-amyloid therapy outside of the general context of this is a new therapy. But from a mechanistic point of view, what are your thoughts?

So I think combination therapy makes good sense and how do you proceed with that when you've got one approved therapy and one still in the development stage. So assuming anti-amyloid monoclonal antibodies are standard of care, they're getting there. But in Canada, we don't have reimbursement yet. So there'll be lots of people who won't be able to afford or access the drug. So you'll still have a population of treatment-naive patients just on symptomatic treatment. But if you enrolled patients on a background of anti-amyloid therapy in your trial, you'd be looking for enhanced benefit over what you would get from the anti-amyloid approach alone. And so that complicates trial design. Nevertheless, it's doable. What I would love to see is a trial where we have patients naive to both therapies enrolled in roughly the same time frame on both treatments. And why do I say that? The risk of ARIA from anti-amyloid monoclonal antibodies is in the first 6 months or so. That's where it's highest. And so if you're past that window of ARIA, you're not going to be able to demonstrate that XPro potentially reduces the risk of ARIA. So if you have people who are already on lecanemab, donanemab and have been on for 9 months a year and then you add XPro, hopefully, you'll see the increased benefit, increased efficacy, but you won't see the mitigation of the safety profile. So it's complicated. I'm sort of rambling here, but you can see there's lots of different ways that one could think about designing combinations.

That's great. Well, I really appreciate everyone joining. And I certainly, from the bottom of my heart, really want to thank Dr. Woodward and Dr. Cohen for their time today and for their continued partnership as investigators. Their experience and their willingness to share their independent perspectives is invaluable, and we're very fortunate to work with them. I also want to thank each of you for joining us. We understand that confidence is earned and our job is to earn it with data, with execution and with transparency. Today was one step in that process. If you have follow-up questions that didn't get to us, our Investor Relations team is available. You can find the contact information on our website or at the bottom of any of our press releases. We look forward to updating you as the program advances. Thank you for your time today and your continued interest and support in INmune Bio.

Thank you. Thanks, Sharon.

Thank you.