Hello, everyone. Thank you for attending today's Fierce Biotech webinar, Alzheimer's Outlook: Neuroinflammation, the Next Step. I understand we have a great number of attendees on today's webinar, and I want to thank InMed Pharmaceuticals for sponsoring this presentation. My name is Phyllis Ferrell, and I will be moderating today's conversation. But before we get started, here's a few quick housekeeping notes. You can access closed captions from the bottom right corner of your video player. And to access the additional resources from today's presentation, you may click on the Handouts tab that's on the left side of your screen. This webinar is being recorded, and it will be available to watch on demand within 24 hours. And last, but certainly not least, during this presentation, please submit any questions you have in the Q&A tab, which you'll find on the left side of your screen.
We know that there'll be lots of active engagement today, and that'll make it more fun. I'm so excited for you to hear from this esteemed group of panelists. They're truly key opinion leaders in the field of Alzheimer's disease, and specifically neuroinflammation. You're going to hear from David Morgan, who's the director of the Alzheimer's Alliance and professor at Michigan State University. You're going to hear from Dr. Marwan Sabbagh, who works and does research and sees patients at the Barrow Neurological Institute as the Moreno Family Chair for Alzheimer's Research. You're going to hear from Dr. Barry Greenberg, who's the associate professor at Johns Hopkins and the editor of Alzheimer's & Dementia: Translational Research & Clinical Interventions. And you're going to hear from Dr. Eric Hsu, who's the senior vice president of preclinical R&D at InMed Pharmaceuticals.
But if you'd like to hear a little bit more about them, you can read their bios under the speakers tab, which is on the left side of your screen. It's important to clarify, though, that each of these individuals are experts and are speaking on their own behalf. With the exception of Eric Hsu, none of the participants in this webinar represent InMed Pharmaceuticals, and their views should not be interpreted as investment advice. So with those housekeeping items, let's get started. Here's our esteemed group. They're also friends and colleagues in the Alzheimer's space. And I'd like to start by thanking all of you for being with us all around the country and even from Canada today. But what is really important for us as we kick this off is that we are in a very new place in Alzheimer's disease research.
It's been 35 years since we've had a new therapeutic launch, and now some of the first disease-modifying therapies are available, at least in the U.S., in Japan, in China, and a few other countries. But that didn't happen overnight. It's been a steady increase in disease understanding and research progress, with exponential increase over the last decade. And for folks that haven't been insiders, they may not have been following along on what seemed like failure after failure after failure to really understand how much progress we've made in the field. So what we're going to focus on today is what comes next. And I know you'll be excited to hear from this group. I'm going to start with Dr. David Morgan. So Dave, you're my mouse guy. What are the challenges with mouse and other animal models in neuroscience and Alzheimer's research in particular?
This has been something the field has been challenged with for a while. Can you tell us about progress we've made and where there's still challenges and where there are opportunities?
Yeah, well, I think one of the most important things about mouse models is what they are models of. For the most part, we don't have a full model of Alzheimer's disease, but we have our models of amyloidosis. We have models of tauopathy. We have some models that may include both features, but those are relatively rare, but it's very important to note that Alzheimer's disease not only is amyloid and tau, it's got lots of other components as well and other contributions from other pathologies like Lewy body pathology, is just one, and so the mice don't completely replicate that, but they have been very good models of things like amyloidosis, and they were very helpful to us in identifying that, in fact, the only treatment that has been able to remove amyloid from the brain of an amyloid mouse that was already there is immunotherapy.
That has turned out to be the first disease-modifying approach that we have for amyloidosis. Another issue with the mouse models is that typically the way they're testing agents is they're testing them as a prevention approach, not as a treatment approach. They're not waiting for the mice to get old and to have mature pathology, but instead, they're treating them before the pathology even starts. While those types of treatments will probably be effective as we get closer and closer to having biomarkers for pre-symptomatic individuals, that's been part of the challenge, has been trying to find out which of those prevention treatments actually will be effective in treating people who already have the disease. A third element that I think is very important in the mouse models that has been largely neglected, in part because of the cost associated with it, is advanced age.
Alzheimer's is not a disease of juveniles. It's a disease of older adults, and to get a 20- or 24-month-old mouse is actually a fairly both expensive and time-consuming approach, and so most models have been looking at very aggressive forms of the disease that occur at a younger age. Interestingly, when we looked in our old mouse models of amyloidosis with immunotherapy, we found the harbingers of ARIA. We did not see that when we tested ARIA immunotherapy in younger mice, but only in the old mice could we begin to see the micro-hemorrhages that now are part of that problem, so I think this is the way that we can improve the models by integrating more pieces of them together and paying attention to the details of how we treat and when we treat.
Oh, it's an excellent point. And actually, for those that may not be close to the acronym, ARIA stands for Amyloid-Related Imaging Abnormalities. How about that?
Good.
I did that well, and those are some of the side effects of the existing disease-modifying therapies, and I didn't realize that we could have seen that early on in mice. Sometimes we think of animal models as efficacy, but models also play a role in safety prediction.
2004, we saw it.
Fantastic. I learned something new. Thank you. So I'm going to shift over to Barry. Barry, the brain is the next frontier. You're a translational researcher. We've heard some of these challenges from Dave, but what do you think about the progress we've made in the field so far? What do we know now that we didn't know before?
We know a lot more now, so I'm not going to take up two, three hours of your time by starting to look at all of that. What I'll do is I'll hit you with a highlight. Over the past few years, we have shown that it's possible to remove amyloid from the brain of a human with Alzheimer's disease pathology. Excuse me. What I found to be stunning that I first saw at the AAIC meeting a couple of years ago in Denver, three years ago, was not only did those antibodies remove amyloid, they also impacted on levels of tau and glial fibrillary acidic protein, so the tau biomarker and the inflammatory biomarker were being reduced by removal of amyloid, and that was just, like I say, that was a stunning moment that has been replicated with every anti-amyloid immunotherapy.
What we know now is that these therapies, they can completely wipe out the amyloid in the brain. And they also have an impact on the rate of disease progression, but they do not stop disease progression in the way that we're analyzing the data by looking at averages among individuals who are in the treatment arm and in the placebo arm. We don't yet have the patient-level data, which is critical. And that's still sitting in the computers of people who are the sponsors of these trials. So we do know that there's limited clinical impact at an average level in these treatment arms, but we know that there are individuals from anecdotal reports of personal experience that do much better than those averages, and there are people who are not responding to these drugs. And that's for a variety of reasons that we still need to figure out.
Missing from these trials is an adequate investigation of racial and ethnic diversity. These trials have been run almost exclusively on white people of European descent. I've actually thanked members of the pharmaceutical industry for being so concerned about people who look like me, but challenged them that they need to do better because the biology, the biomarkers are different depending upon race and ancestral ancestry. I'll stop there.
I think it's an excellent point that you made about the heterogeneity of the disease in general and that we've got a lot more to learn. But the diversity aspect is critical as well. And I know it's something that people are really focused on right now, but it's too late, I think, is a point that you're making. And so we need to speed it up a bit. I know clinical trial enrollment is one of the things that actually makes the research quite a bit slower than it could be for those of us that are really waiting for more therapies to come through. So I'm going to shift over to Dr. Sabbagh, Marwan. While none of us want to doom mice to cognitive impairment, what we really want to do is cure Alzheimer's disease in people.
You see patients every day, but you also run late-stage clinical trials. You've run many of them. What have you seen in the last decade that makes you hopeful or the opportunities that we see in front of us?
Phyllis, thank you for including me. I'm grateful to be a part of this panel. I am a clinical neurologist at Alzheimer Trialist. I have done this. The one thing I will say to you that's relevant to your question is that we keep learning in an iterative manner. We now include patients and select patients on the basis not of clinical criteria, but biomarker criteria. It turns out when we still, to Dave's point about the injection, I still have your slide, Dave, from Nature from 2000. I still have that slide, is that we used to enroll patients just on their clinical diagnosis. It turns out to be up to a quarter of the sample didn't have the target pathology.
So in an iterative manner now, we are learning to select patients more carefully, select them by safety, make sure they don't have micro-hemorrhages if they're getting a mAb, select them by their genotype, select them by their biomarkers. And so the ability to demonstrate clinical efficacy signal in our target population has gotten more cogent because we now have selected our patients better.
Oh, it's an excellent point, and for the group listening, a mAb is a monoclonal antibody and refers to some of the disease-modifying therapies that are available today, and Marwan, I remember running the solanezumab studies, Expedition One and Two. We didn't have amyloid selection criteria there, and we were wrong 25% of the time about someone having amyloid, even with extremely experienced raters and clinicians. It's an excellent point. This disease has to have clinical and biology.
Fundamentally, I think we, of course, diluted our efficacy signal because we didn't have patients having target pathology.
Yeah. The other thing we learned there, if I recall, Marwan, is that we started using PET imaging. And we actually learned that this disease starts in the brain with pathology 10 to 20 years before symptoms. So we've had a pretty late view of this disease until recently with some fantastic technology improvement in the diagnostics. I'm going to shift gears a little bit. I want to go over to Dr. Hsu, Eric, who's joining us from InMed Pharmaceuticals. And this is a new space for you all, Eric. I mean, Marwan, Dave, and Barry, we've been hanging around in this space for a while with a close group of colleagues, but InMed's coming new. So how did you come to find yourself in the field of Alzheimer's disease research and development?
Phyllis, thank you for having me on the call. As you said, we kind of dabbled into the Alzheimer's space. We actually started with the ocular space, looking at neuroprotection. Initially, when we were studying glaucoma, we had these in vitro assays set up that's looking at neuroprotection using elevated pressure as insult to retinal cells. We were able to identify a specific compound that can protect these cells. At the time, we asked the question, can the effect be translated to other neuronal cells? We then set up another different assay. This time, we use neuronal cells and using amyloid beta as an insult. Surprisingly, the compound we thought would work didn't work. Instead, through our screen, we identified the INM-901 compound as the most effective compound to prevent the amyloid peptide-induced cell death.
And these compounds are shown to be able to produce neuroprotective effect. During the process, we actually saw another interesting feature of the compound. Once the cells are exposing to these compounds, we see the neurons start to extend and branch out. And this is a process, what we call neurogenesis. So what we found is the 901 compound, not only can it provide neuroprotection to the neurocells, but it also allows it to induce neurogenesis and increase the neuroplasticity. And that's how we got into the Alzheimer's space. And what's interesting about this compound is that it's a small molecule. It's able to penetrate blood-brain barrier. And now we're able to formulate this into oral formulation. And we have done studies. Animal studies show that this compound is stable and also has a good bioavailability in the brain.
We're very excited about the progress we're making and then to study this compound in the Alzheimer's space. Thank you.
That's excellent. Yeah. We need more. We know that while we have some new therapies available today, it's not enough. And we're going to need more. So let's actually pivot to neuroinflammation specifically. And I'll remind anybody who's listening to the webinar to please continue to put those questions in the Q&A. So we all know that chronic inflammation is bad. It's something we've heard about with multiple therapeutic areas. We hear about it in plant-based diets. We even see it on the cover of women's journals in the grocery store checkout. But I don't know that I understand everything about what it means for the brain. So I'm going to kind of run in the same order again. And so, Dave, I'm going to start with you. What do you see as the pathophysiological effects of chronic neuroinflammation? How are they studied?
Can you see the impact in animal models?
We've really been looking at the role of inflammation in Alzheimer's disease since the mid-1980s. The pathology of postmortem tissues was identified as having a pretty substantial neuroinflammation activity that was around the amyloid plaques and sometimes around where the tau neurofibrillary tangles were located. And so Pat McGeer and Piet Eikelenboom recognized that this could well be contributing to the ultimate neurodegeneration that was occurring in the disease. A second piece of evidence that came along in the 1990s was the identification that a class of drugs called nonsteroidal anti-inflammatory drugs, these are the aspirin and ibuprofen type of compounds, that people who took these at high doses for long periods of time ended up having a pretty substantially and very consistent reduction in their risk of developing Alzheimer's disease. And so this suggested that it was the effects of the drugs.
We now know that's probably not the case, but that also pointed to inflammation as being very important. And then more recently, in the 2000s, we started seeing that the genetics of Alzheimer's disease, we were looking at the genes that modify the risk. And many of these genes are found in the innate immune system and only in innate immune system cells. So this is telling us that there's some causal linkage between inflammation and the disease itself. And then finally, we've noticed now, again, epidemiologically, that people who have pretty severe systemic infections that activate the immune system, things like COVID, these people appear to have increased risk of developing dementias. And Alzheimer's is probably a part of that focus. So all of these things have really caused us to really look at inflammation as possibly beyond amyloid and beyond tau, another potential drug target.
Yeah. Having something that's druggable, a target that's druggable, is a key part of the step here. So I want to build on this idea of where neuroinflammation is in the amyloid cascade. Because Barry, you mentioned it already a little bit about amyloid and tau. And you'll remember the days like I do where it was fighting, is it amyloid, is it tau, and now we realize it's both, they're part of the same cascade. Where does neuroinflammation fit in? Does it go amyloid-tau neuroinflammation? Does neuroinflammation come first before amyloid? Do we know? What do we know? I'll toss that one. That's a toughie, I know, and I'll toss it to you.
That was not all that toughie because we just have to understand the limitations of our assumptions. We have a tendency to think in a linear manner, and biology does not think in a linear manner. It's multidimensional, and there are things that are happening at the same time. It's inherently heterogeneous. The disease, the progression of Alzheimer's disease is clinically, pathologically, and mechanistically heterogeneous. So amyloid is involved, tau is involved, and inflammation is involved. Other things are involved as well. So it's not a linear pathway. We have to correct our thinking. This is one of the reasons that patient-level data is as important as it is to inform precision medicine approaches so that we can ask, does this person require an inflammatory intervention or not? The other thing to consider is that the disease does not happen homogeneously within an individual's brain.
It starts in one region of the brain, and it spreads to another region of the brain and continues a progression, again, with some degree of heterogeneity. And this incurs inflammatory responses, which are initially thought to be helpful in order to keep some inflammation in check. But with the progression of the disease and the fact that the degeneration eventually wins the battle with the resistance to disease progression, it becomes destructive. And so if you think about that and you recognize that different regions of the brain are actually living in the same temporal space at different levels of the progression of the disease, if you don't have a drug that is exquisitely sensitive to the damaging inflammation, then it's going to be helpful in some regions of the brain and harmful in other regions of the brain.
We don't know what that's going to translate into clinically. What this all does is it opens opportunities for combination therapies once we can get our heads around the precision medicine and understand the inflammatory cascades as they stack up next to the other ones that we like to think of linearly, but shouldn't be. And this also opens up an opportunity for drug repurposing, which is already happening where drugs have been approved for other disorders and are being brought in for testing, not necessarily at the same doses as for the prior disorders, but to intervene with the pathogenesis of Alzheimer's disease. It's just important to keep in mind that inflammation is not uniform in Alzheimer's disease brains.
Oh, it's fantastic. And I get this visual of kind of a disease cascade with kind of in a fire where different spots are hotter than other spots in the brain. I think it's an excellent.
Yeah, and going with that analogy, which way is the wind going to blow next?
The ability to identify what each individual patient needs. So with that, Marwan, at Barrow, you see patients. You've got clinical trials. Can you see the effects of neuroinflammation in humans? Can you see that? Can you treat it? And there's a lot of data coming out right now, including Karolinska's FINGER study and some of the work that's being done now to replicate that worldwide. Is this something that we need drugs for, or can we be intervening in non-therapeutic ways? Is that sufficient?
We would love to, ideally. The data is not very strong on non-pharmacological effects to treat neuroinflammation. We posit it, we hypothesize it, but the data doesn't support it quite yet, and to Dave's point, we actually tried the COX pathways. That so far largely has not been successful, so now we're looking at other mechanisms. When you're talking about microglia activation, we're looking at TNF-alpha. We're looking at interleukins and other things, so other targets of inflammation are being looked at and targeted and developed, but for the most part, there is no lifestyle or dietary approach that we know of that can absolutely reverse neuroinflammation. I do want to say that even measuring neuroinflammation, of course, is becoming a thing of itself. We have CSF markers now, plasma markers, even now, PET with TSPO to measure it.
But these are still early days in even having the ability to measure in neuroinflammation, much less treat it.
I want to pause there because I think that's really, really critical. Dave was talking about druggable targets. Barry's talking about precision medicine. One of the reasons that we're able to be successful where we are right now is because we do have biomarkers for amyloid that everyone's aligned upon now, at least pretty well aligned. So are you seeing that progress, Marwan, in biomarkers for neuroinflammation? How far away are we before we ever go, "Yeah, we know what the neuroinflammation biomarker or biomarker panel is"?
We do have some signals with GFAP, YKL, and others, but they have not made their way into clinical practice. We don't use them routinely. We don't know trend effects quite yet. In other words, if I drop a biomarker on the basis of a clinical treatment efficacy signal, that logically says that the drug is working. But those are easy, obvious things to answer. We're still trying to answer those.
Yeah. It's a little less mature than amyloid pathway, but I'm convinced we've got the right people working on it. So Eric, INM-901, you mentioned. You've actually looked at inflammation and neuroinflammation a little bit. Can you tell us a little bit about the studies that you've done there, recognizing they're very early and what you're seeing?
Sure. Let's start from the cellular receptor 901 interact with. What we found in our study is that this compound actually interacts with several receptors, not just one receptor. So it's an agonist for CB1 and CB2, as well as PPAR-gamma. And CB1 are often found in the central nervous system. It can be found on neurons. CB2, on the other hand, it's associated with the immune system. In neurodegenerative diseases such as Alzheimer's, one often finds that CB2 is upregulated, and that's because of the active inflammation that's going on in the brain. And again, PPAR-gamma, it's also been shown to be important to modulate immunity. So we believe that in the 901, it's actually acting through CB2 and PPAR-gamma to modulate already over-activated microglia cells and turn them from an inflammatory state to an anti-inflammatory state.
So that's where we think how 901s impact neuroinflammation. In our animal study that we did, we used an amyloidosis model, which is a 5XFAD. It has five different mutations that accelerate the accumulation of amyloid beta in the brain and develop some symptom that's similar to Alzheimer's. In this model, initially, we conduct a short-term study. We treat the mice with 901 compound for about three months long. And at the end of the study, we assess their ability to various behavior functions. And what we found is when you look at locomotion, memory, cognition, the 901-treated mice would behave more similar to a normal mice than a diseased mice that are treated with a vehicle. Interestingly, when we look at their brain in the cortex region, we found a decrease in pro-inflammatory markers such as GFAP.
When we look at gene transcripts in the brain as well, we found a decrease of pro-inflammatory signatures such as Toll-like receptor 2, CD33, IL-8. All these genes have been downregulated, so it looks like in our study, we're seeing a decrease in neuroinflammation in these models. We recently conducted a long-term study where we treat the mice for seven months long, and what we found is from a behavior side, we're seeing similar outcomes as what we're seeing in the short term, so the data coming from a long-term study is consistent with the short-term study. Not only that, we were able to increase the animal number to achieve statistical significance of these outcomes and also dose response, so we're very excited about the data we're seeing, and we're continuing to do molecular analysis from the long-term study.
Hopefully, we'll have those data pretty soon in a few months, in short time.
That's great. I mean, I'm going to kind of try to filter in some of the questions that I see coming in as we have this conversation. And one of them, you guys have addressed kind of generally already, which is how is studying drugs in mice give us a clear and comparable view of human brain biology. But let's specify that to neuroinflammation. And I don't know if Dave or Barry, you want to kind of react to how we see the mouse models being able to inform our human studies specific to neuroinflammation and why you think it's still something we need to do. We don't just throw out the mouse models, right? But how do we use them? And I don't know if you want to react to that. Dave, you want to go first?
Yeah. So I think one of the things that we've started to do now is to take some of these genetic risk factors that we know that there are gene variants that can modulate your risk for developing Alzheimer's. And we're crossing them into our mouse models of amyloidosis and tauopathy. And we're trying to find out how do those genetic risk factors modulate the primary pathologies of Alzheimer's disease and, in particular, interact with the neurodegeneration that is secondary to those. And obviously, this has led to a study that's presently going on looking at a protein called TREM2. TREM2 has variants that can increase by threefold your risk of developing Alzheimer's disease.
By using a combination of knocking out TREM2, which means eliminating the gene, or putting in mutant forms of TREM2, substituting into the mouse model the human TREM2 variants that cause the disease, we're starting to understand how this is regulating amyloid and tau and the interactions between amyloid and tau and their overall effects on neurodegeneration. This has led to some studies that are now trying to activate the same pathway that TREM2 activates inside neurons. This is a way in which the mouse models are informing us and leading to clinical trials in human beings.
I always love to have you guys to myself, which I kind of do today. So you mentioned genetic. Do we think that APOE4 status has a neuroinflammation impact? We do.
Yes. I'm quite confident that it does. Yes.
So we think part of the risk that we see with someone who is an APOE4 homozygote is that they have a greater risk for a neuroinflammatory response?
Among a number of other things, yes.
Barry's giving me the timeout. Oh, I hope we get a good debate going. What do you think, Barry?
I'm not going to be debating. I'm just going to be stating an observation of fact. The APOE4 does have an effect as everyone is speaking of. But again, it is based on whites of European descent. The effect of APOE4 varies in other races and ethnicities. And you are much better off if you're carrying an APOE4 gene if you have a Y chromosome than if you're a woman. So the biology is a developing area. We don't fully understand what APOE4 is doing or what all of these other confounding issues are. And that's new knowledge, by the way.
Yeah. So we think it's an inflammatory impact, but we actually can't say for sure if we don't generate the data in a diverse population.
Yeah. Yeah.
Marwan, you were nodding your head. What are your thoughts on, or maybe I should ask you the question, what would you like to see out of an INM-901 once it hits the clinic? What would you want us to be looking at in neuroinflammation clinically?
So, Phyllis, I disclosed to Eric yesterday that I have some. I can't specifically comment about INM-901 because I may have a conflict.
Yeah. Just in general, if you had a neuroinflammation therapy, what would you want to see?
We definitely, Barry's journal publishes the Jeff Cummings State of the Clinical Trials pipeline every year. There it is. It's right on his desk.
Never leave home without it.
Never leave home without it. You know, Barry, probably a smart call. The reason I say that is if you actually look at the way he writes the large deal, he actually also has a graph talking about the categories of therapeutic targets. Neuroinflammation as a therapeutic target grows year over year. I think there's now 27 compounds or something like that. Right, Barry? I think that's what he last said. It's a lot. What I'm saying to you is that neuroinflammation fell out of favor once we couldn't achieve anything with the COX pathway. It's coming storming back, not just with the CB2 pathway, but with repurposing of other drugs from other indications. You're seeing a lot of different targets. You're even seeing the idea that GLP-1s could have a neuroinflammatory response. My point is that it's come back in vogue in a big way.
A lot of people are excited on targeting neuroinflammation in a variety of different ways. We do think that this is going to get a lot of traction.
So you think a drug for neuroinflammation could have a really big impact on the field? Or let's say it better, multiple drugs for neuroinflammation could have a big impact on the field.
100%. In fact, I have grants investigating it myself.
Yeah. It's fantastic. So you actually stole my next section, which was to talk about Cummings Paper. That's okay. That's why we're friends. And so that is the paper that Barry just held up and Marwan referenced. It's actually in the journal that Barry's an editor of, which is Alzheimer's and Dementia Translational Research and Clinical Interventions. And this is an annual report done by Jeff Cummings, which you can find pretty easily. We now have 127 clinical trials being conducted across 14 different mechanisms of action and targets. This is such a significant increase from years ago. I'll put a plug in for clinical trial recruiting and participation. It's probably the only thing that's slowing us down in the field right now. Well, maybe that and biomarker confirmation. So let's talk about these drugs in development. And Dave, you've discussed the challenges in mouse models.
Do we have enough diversification? Does this diversification make things more difficult? Do we have enough models? How do we match the right model with the right mechanism for each drug?
It's not always as straightforward as you might like it to be. One of the problems is we do have multiple pathologies in Alzheimer's, the core pathologies of amyloidosis and tauopathy. Most of the time when we're studying these drugs in the mouse models, we're studying just one of those core pathologies at a time. What we have found is that some of the manipulations that might benefit amyloidosis that are affecting neuroinflammation actually exacerbate tauopathy. It's going to be very important to both test in both kinds of models any drug that's going to modify innate immune activity. I think it's also going to be important to have some combined models that we look at so that we can see the effects on both of those pathologies with the same sort of treatment.
It's very plausible that there may be different stages at which different manipulations are more beneficial than in others. And I think that's going to be something we're going to probably have to work out in a mouse model first before we start subjecting humans to some of these manipulations at different stages of the disease. So I think that it's going to be helpful. We'll find out a great deal. Genetics are really pointing us in certain directions. And in some cases, it appears that it's a decrease in the innate immune function that's associated with increased disease risk. And these are things we're going to have to really work through on a very detailed basis.
Yes. And we have a question in the chat that is kind of one more dimension, right? You've got the right model. You've got the right mechanism. Do you also have to think about it in terms of stage of disease? Can this microglial activation be beneficial or harmful depending on where it's used in symptomatic, asymptomatic disease? Is that another dimension that we need to consider? Dave, you can take that one. Or Barry, do you want to jump in on that one?
I'll just comment briefly. When we look at prevention treatments, okay, so we treat the mouse before the pathology, it appears that a certain amount of activation of the innate immune system is helpful. In fact, immunotherapy is activating the innate immune system, and it's clearing amyloid, and so if what most of these genetics are doing is actually preventing the amyloidosis from even getting off the ground, then that will tell us that that would be a stage when we might want to boost innate immunity. At the same time, we suspect that the inflammation may be mediating some of the effects of amyloidosis on the tauopathy and exacerbating the tauopathy, and that's a stage of the disease at which we might want to tamp down that innate immune reaction and target it as well.
One of the problems is evolution never had an opportunity to select what the innate immune system did in an Alzheimer's brain. There was no genetic benefit to living a little bit longer when you're past the age of 70 or 75 and you're developing dementia, and so we're activating innate immune programs probably in a rather haphazard fashion, depending upon what the signals are that amyloid is eliciting and tau is eliciting in the brain that are modulating the innate immune cells that are in the brain, and some of these things may be beneficial. Some of these activations may be harmful at the same time, so we really need to dissect this with a very fine-toothed comb in order to really understand what's going to be the best strategy to follow going forward.
Plus, we need more biomarkers and much better than TSPO, which really hardly is a biomarker at all, as far as I'm concerned. So there.
So Barry, do you have a reaction to kind of targeting stage of disease here as well? Or I mean, obviously, you've made the case for diversity.
I think doctors need to be doctors. It's one of the things that I have found particularly enriching since I moved to Hopkins six years ago is I'm interacting with people who actually are making case reports that they have experience with every week in a time when we're having disease-modifying therapies being developed. We're talking about the specificities of each individual patient and not about Alzheimer's disease as a bucket. Alzheimer's disease as a bucket is a concept. It's not what the doctors face when they have their hands and their discussions involved with these patients. When you think, I appreciate you smiling, Marwan. Thank you for that. It depends on the drug. It depends on systems pharmacology, which is going to differ in humans than it does in mice.
It's going to differ from one human to another depending upon the other drugs that human is taking, the polypharmacy that is part of the aging process that complicates the initiation and progression of Alzheimer's disease. The differences in side effects depending upon who the patient is and what the other things the patient is doing in his or her lifestyle. So we have to understand this heterogeneity to the best that we can. We have to learn from the clinical data. We have to learn from the patients and their caregivers. They must be involved in this developing medical story every bit as much as their physicians are involved. And we have to recognize that these therapeutic complexities are also creating major challenges. We haven't even brought this up in this discussion yet. And I can't say much more about it than I'm going to in my next sentence.
Major challenges in data analytics.
So Barry, thank you. And I'm going to have to thank you for this because the next time Marwan and I are in a debate, he's going to say, "Let doctors be doctors." And he's going to throw your quote right back at me.
He's absolutely right.
But Marwan, how do you have this conversation with your patients? Whether it be about neuroinflammation or the heterogeneity of Alzheimer's disease and related dementias, do you think about multiple pathways and biologies when you've got a patient right in front of you?
Absolutely. And Barry, I was smiling because right after this webinar, I'm going to clinic and I'm going to share the very things you just talked about with patients who are making life decisions on the basis of this. So we can have these discussions in a theoretical fashion, but they do have a strong applied endpoint to them. Patients are making decisions. Family are making decisions. To your point, Phyllis, we have limitations in what we can do, right? So when I talk to patients nowadays, I give you three options. One, symptomatic therapies: the cholinesterase inhibitors and memantine. Two is symptomatic therapy plus MAB. But remember that 80% of patients are not eligible for mAbs, right? 80%. They're too impaired. They have a pacemaker. They read Dr. Google and they're scared to death. They have too many microhemorrhages. They're 4/4s. Many, many reasons to not get the mAbs.
And then the third option is symptomatic therapy plus clinical trial. I'd love to talk, and my patients read Dr. Google every day. And so they give me this, they're walking into clinic with a stack of, "I read this and I read that." I love to talk about inflammation. I love to talk about multiple targets, but they don't translate into something I can write a prescription for or put in my EMR. I can only say, "Yeah, that's a good idea at this point." So we're still early. Even though we now have two major breakthrough drugs, we're still early in the therapeutic days. We're in the beginning of transforming Alzheimer's from a terminal disease, as you and I know it, to a chronic disease. This is the diabetes and HIV of our time.
We will, all of us, all five of us, achieve that in our lifetime, making it a chronic disease. Will I cure it? Sorry, you guys can close your ears. I don't think we'll cure Alzheimer's in our lifetime. I think we will make it a chronic disease, much like we did with diabetes. But the endpoint will be that people will live good qualities of life. They will retain their sense of self. They'll retain their agency and autonomy and their voice and their ability to make their own decisions. And that is very important. Their quality of life will be retained. And so I tell you that I love to talk about lots of targets, lots of shots on goal. I wish I had those in my tool bag.
Oh, I think it's fantastic. For every single person that has had this in their family, we know that what we have right now isn't enough. And so, Eric, with that, I'm going to transition to you, but I'm going to ask you a question that maybe you weren't expecting. One is, of course, do you target multiple pathways and biologies? And you should answer that. But more importantly, as you're listening to this conversation, how does it feel to come join the Alzheimer's community in terms of being at a time point, at a juncture that's just so critical, where there's so much opportunity? So maybe two questions embedded there. What are you doing and how do you feel about it?
Let's talk about the first one, multiple actions or mechanism of actions, specifically related to the 901 compound. Earlier on, we talked about not just CB2 that 901 is going after or interact with, but also interact with CB1, PPAR gamma. Also, if you recall what I talked about earlier in in vitro screening that we did, that's just a neuronal cell in absence of any immune cells. In those cells, 901 compound was able to provide neuroprotection as well as neurogenesis. When we look at the animal data that we generated, we see gene profiles that related to reduction of apoptosis, caspase-3 were reduced, Bax were reduced following treatment. We saw neurogenesis gene like brain-derived neurotrophic factors increase and all that. It is very possible that this compound can go after multiple mechanisms other than just neuroinflammation. We're excited about that.
We're going to see what happens, and the more study we're going to do, why we're pushing our development forward, we're going to find out these answers. The second question is, sorry, can you remind me again the second question?
How do you feel about joining this fight?
Very excited. At this point, we do have therapies that remove all amyloid beta. It's shown to work in a clinic to some extent, but it has also allowed resources for different areas to deal with different mechanisms of this disease. And I think we're entering this at the right time. It's allowing us to have experts like David, Barry, and Marwan to kind of provide these insights and help us focus our effort on the right study to do and to push the program forward.
Yeah. I will say I don't think there's a better time to be in Alzheimer's disease research than right now because I think we're on that curve that's just an exponential growth of the biology learning. So I'm going to shift gears a little bit because we've got a few more questions in the chat that I'd like to get to, at least as many as I can. I'm going to start with a question I don't know that I know the answer to. So maybe, Barry, this is some of your question about the challenges or Marwan. Are pharmacogenomic specialists, for example, pharmacists, consulted during the drug development process and prior to prescribing the disease-modifying treatments? I don't know the answer to that.
So Marwan, first, the person who asked that is a protégé of mine from when I was in school.
Oh, please.
I hope you're well. I wish you well. But absolutely, pharmaceutical pharmacogenomics. But this is in the drug development side, not the post-approval side. We are using these paths all the time. And we actually need the pharmacists to help us with drug development. In fact, they're always part of the team when we're developing these things. So the answer is strongly yes.
Okay. I'm going to throw in another one. There was a mention of COVID infection being involved. Does anyone want to elaborate on the newest thinking regarding neuroinflammation and long COVID?
I'll let Dave, but I want to tell you that we are actually. I just got a large grant to look at that. And it seems like there is, so far the data suggests, there's no evidence of viral fragments in the CNS, but there is a robust, huge inflammatory response to the virus, which seems to be the vector or the mechanism by which we're seeing the cognitive impairment, but it's still being explored.
Anybody else? Anything on COVID?
Yeah. I'll go ahead and add to that. There's a fair amount of epidemiologic evidence that other major infections that require hospitalization will increase risk. And in particular, if an individual suffers from delirium, which is often associated with major systemic infections. And delirium was very common in people who had COVID. There's also some discussion that one of the routes for a virus to get into the brain is through the olfactory system. And the olfactory system then connects directly to the hippocampus, which is where essentially memories are initiated. I don't say that's where they're stored, but if you remove the hippocampus, you can't learn anything new. So we know that that is a place that's also quite degenerate in Alzheimer's disease.
So there's biological connections from COVID being a respiratory illness affecting the upper respiratory system, infiltrating into the CNS, and possibly finding its way into those brain regions that are particularly sensitive to the pathologies of Alzheimer's disease. I agree with Marwan right now. We still don't have enough evidence. The time lag in this may be quite substantial. If you have people who got it in their 50s and it accelerates by five years, you may not know for another 15 years. So I hope Marwan got a really long grant for this particular type of a study.
Yeah. I think the other thing that you guys are really hitting on is this importance of an accurate diagnosis. Sometimes we interchange the word Alzheimer's disease with dementia. And we use those kind of interchangeably, and they're not necessarily. So that ability to kind of get an accurate pathological diagnosis. I do have a question. Will there be a recording of this available afterwards to those attending? The answer is yes. I know the answer to that one. And I am going to, let's see. Oh, let me ask this one, and then I'm going to pivot to our closing comments. What do you all think of the new FDA guidelines that this says downplay functional endpoints versus cognitive when considering commercial approval and MCI early AD? Probably better stated, a balance of a biological and a cognitive functional endpoint.
I think I know you're going to answer, but what do you guys think of that? Barry, you want to jump in? Marwan? Marwan's got his eyebrows up. I know he wants biology and the diagnosis, right?
I think the problem is at very early stages, you don't have functional deficits, so there's nothing to fix. That would be my interpretation. If you're scoring—
The earlier you go, the less you can rely on function or even cognition for that matter.
We know that a big problem is the loss of capacity to overcome challenges to homeostasis. That's aging, basically. And we have reserve capacity in almost all systems. And when we look at functional readouts, there's a fair amount of reserve capacity there that we need to get rid of before we start to see evidence that there are these functional deficits. And so we've argued that Alzheimer's is largely, at least initially, a cognitive disease. I don't know how absolutely true that is. But yet, that would seem that if you're looking at these pre-symptomatic or early-stage MCI conditions, the functional readouts, there just may not be enough dynamic range in the outputs to actually detect an effect.
Other reactions?
Function is also very heterogeneous. Probably more so than cognition is because people have different levels of function in their lifestyles depending upon who they are and what they do. And if someone's functional output is driving to the drugstore and home, that's different from someone who is driving to work and engaging in demanding activities and coming home. And there's different levels of resistance, resilience to loss of function. So it's hard to measure early in a disease. I think Dave was exactly right.
It's excellent. We have to close. I know we could keep going for a while, and I'd like to give you each one minute or quick statement of what is exciting you about the field right now, what makes you really hopeful. Eric, I'm going to start with you.
Yeah. Thank you. I think we're at the stage where we start to understand this disease better. Previous focus was always on amyloid beta, and now we're starting to explore different, start to understand the biology a little bit more, and also, there is a lot of different mechanisms that we're looking at and to intervene with these diseases. So I feel like we're at the right time to make some changes or make a difference in treating this disease. So yeah, that's the INM-901 program for InMed's early, but we're excited to see where it's going to take us for sure.
We're excited to welcome you to the field. We need more Alzheimer's warriors. Dave, what makes you hopeful and excited right now?
I think the fact that we're on the cusp of having some drugs that will possibly remove the tauopathy. I think the first step was to get rid of the amyloidosis, but we're pretty convinced that's probably not going to be, at least for everyone, the final stabilization that we're all looking for. And I think that there's a couple of approaches, some of which we just saw a couple of weeks ago in Madrid, that we're demonstrating that you can remove pre-existing tau pathology as measured by PET scans. To me, you add that with amyloidosis, and if you get an inflammation drug on top of that, you get a resilience drug, a memory-enhancing drug. We're not going to treat this disease with one drug. And we don't even treat hypertension with one drug.
There's room for a lot of different novel approaches that will ultimately, I think, be synergistic in helping to arrest progression of the disease.
Thank you, Dave. Barry.
Yeah.
What are you excited about?
This is the first time in our lives and anyone's lives that we're actually analyzing clinical data for disease-modifying therapies. And you used the word, "We're on the cusp." We're on the cusp. We're on the precipice of massive new knowledge about this disease that's going to happen over the next few years. And we can't even imagine what that new knowledge is going to do for us. But I think we need to take the concept of precision medicine to heart and actually take a page out of the cancer playbook. You can't cure all cancer. There used to be the war on cancer. Well, you can't cure all Alzheimer's disease because it's a heterogeneous set of symptomatologies. So we likely will not find a cure for all cases of Alzheimer's disease.
But let's keep in mind, if we can just figure out a way to treat successfully 10% of Alzheimer's patients, first of all, that's going to open that massive knowledge doorway to treating the others. But just 10% is equivalent to 100% of all individuals who are dealing with Parkinson's disease. So these are massive numbers. And the progress that we're making now is going to be fundamental. And I hope it does happen within our lifetimes, Phyllis. Some of us are older than others.
Marwan, what makes you hopeful?
What makes me hopeful is that I want to see all the memory care facilities go out of business because we've done our job so well. That would be awesome. As I said, we're in the beginning of the transformation, and we will be doing a chemotherapy multi-drug cocktail. To Barry's point, the 16 endophenotypes, it will be precision medicine. We will not be using one approach for everybody, and we will have to come up with different approaches based on different people, so there's a lot more unknowns, but we're finally moving the needle in terms of therapeutics. It's very exciting.
I can tell you what makes me hopeful and excited is that we've got big brains like yours leading this battle, all of you, and also big hearts. A big thank you to our panelists today. We are at a critical juncture for Alzheimer's research. There's no better time to get involved, to invest. Thank you to all of you that joined today on the livestream, those that are watching on the replay. Just as a reminder, this recording will be available on demand within 24 hours. We greatly appreciate your participation. We're sorry we couldn't get to every question, but we will try to follow up. For more information on InMed Pharmaceuticals and the INM-901 program for Alzheimer's treatment, please download the available materials that are listed in your handout section or visit the website and use the links on the webinar registration page.
If you wish to speak directly with the company representative, contact details for Colin Clancy, the InMed Vice President of Investor Relations are also provided. Thank you, everyone. Let's go get this disease.