Talking Biotech Podcast - Targeting Chronic Inflammation Via the Inflammasome - Dr. David Bearss

Hi everybody, and welcome to this week's Talking Biotech podcast by Calabria. The subject of inflammation is coming up a lot lately, and we see discussion of inflammation as kind of being hand in hand with a number of different disease states, particularly in the area of neurobiology and neurodegenerative disease. We've seen even just today, I read an article about Alzheimer's and localized inflammation, that kind of thing. We also see it showing a lot in rather dubious websites and social media that says you can cure your inflammation by drinking lemon water with whatever in it, you know, or whatever. And so, all of these different areas, we're seeing the discussion of inflammation and how it may really be something that we need to think about in terms of potential therapeutics. At the same time, how do we sort out what's real and what's not? And so, today's guest is part of the therapeutic end in coming up with new ways to treat what looks like What inflammation's contribution is to long-term disease. So, we're speaking with David Beers. He's the CEO of Halea Therapeutics. So, welcome to the podcast, David.

Yeah, thank you. It's great to be here.

Yeah, I appreciate you being here. And, you heard in my introduction that this is really an amorphous subject for me because I think about inflammation, I hit my hand with a hammer, I see inflammation. But, someone will tell me, you know what's wrong with you? You're tired because you're suffering from chronic inflammation. I had a friend of mine who's a chiropractor tell me this once that I had magnesium deficiency and I had chronic inflammation. I'm like, all right, well, I don't know. Well, so, what is inflammation?

Yeah. It's a great question. And, like you said, I think right now because of discoveries that we've made just in the past few years, it's become kind of a buzzword and we're linking inflammation to a lot of especially chronic diseases. So at the end of the day, inflammation comes in 2 forms. It's acute inflammation, which is what you talk about when you hit your thumb with a hammer, you twist your ankle. And, you know, you go to medical school and they'll teach you that inflammation is associated with redness, swelling, heat, and pain. That those are the hallmarks of inflammation. And that's really the— that is acute inflammation. And acute inflammation is the body's normal response to damage or injury. It's part of our innate immune response. So when our body has something that goes wrong and we have a signaling mechanism to tell the immune system, there's a problem here, inflammation is what is the result. And it's the goal of inflammation is to identify and to stop the spread of whatever caused that problem. And it's supposed to happen acutely or quickly, and it's supposed to resolve and go away. And, you know, I'm old enough that I was taught back in the old days when I was a graduate student, I took an immunology course and they taught me that chronic inflammation was just the failed resolution of acute inflammation. So you had an inflammatory response that just never went away. And what we've discovered over the past few years is that's not exactly right, that there is actually a difference between how chronic inflammation gets started, how it's propagated and maintained, and how it's different than acute inflammation. And so this discovery of the difference between the two, where we've always kind of just thought they're exactly the same, it's just one persists and doesn't go away and the other one is supposed to resolve. It turns out that there's some subtle differences and those differences really seem to be important in a lot of diseases. And so as we've discovered this biology, we start to look and say, well, where can we find this? And it turns out almost every place we look, we find it. And so it's become a really interesting area. And as you mentioned, there's, I think, you know, you can attribute almost everything to inflammation, but I think that we're starting to understand the reality of what it does under different conditions and now how to target it and how to how to therapeutically go after chronic inflammation.

Yeah, but this is the thing that I think about is, so is it always a cause or an effect? So, or is it a little bit of both? Like, you know, if you have chronic inflammation, that's because something else isn't right, but does it, the inflammation response over time, really trigger a separate suite of physiological change?

Yeah, and it's a great question. I think the answer is that inflammation combined with something else is usually the bad thing. And so, you know, for example, you brought up at the outset that we're starting to realize that a lot of neurodegenerative diseases, so Alzheimer's and Parkinson's and ALS and Huntington's, all of those diseases have a very strong inflammatory component to them. So in the old days, Alzheimer's, for example, we used to think, that Alzheimer's was the accumulation of these plaques in your brain, beta amyloid deposition that led to the, you know, we used to think, ah, it just clogs up the works up there and stops you from being, your brain from functioning properly. Well, what we know now is that there's lots of people that have plaques in their brain that don't have Alzheimer's. And so it's not just that, it's the plaques plus inflammation that causes the disease. So, and the same thing, like for example, in In cardiovascular disease, we used to, you know, you probably have had a lipid panel run and know your cholesterol. You know, the older we get, the more concerned we are about those types of things. And so you measure your total cholesterol and your high and low density lipoproteins and, and you get a sense of, of, you know, what your cardiovascular health looks like. Well, it turns out that, that it's not just cholesterol buildup in your arteries, it's cholesterol buildup plus inflammation that causes the problem. So, so it's always kind of this. This plus this equals something bad. And so I think it can be, it certainly is a driver in many diseases, but it's a driver when combined with something else that is really causing dysfunction. And if you think about it, the problem with inflammation is, with chronic inflammation, is that when the immune system gets activated and it can't find a problem, it will create a problem. And so it, You know, it's supposed to take care of something quickly and then supposed to go away. And if it stays on long enough, it's going to go looking for things. It's going to say, well, you know, I got activated for a reason. There's got to be some problem here. I'm going to go find something. So, so that seems to be the issue is that, that, you know, and I tell people when we're young, our immune system is our best friend. It protects us from infections and, and, you know, but as we get older, it's actually actively trying to kill us, that our own immune system is actually hurting us. And, and You know, I would guess that, you know, 40-plus years ago when HIV was kind of, you know, we realized we had a virus that was killing our immune system, you know, we poured money in to better understand our immune system. And 40-plus years ago, I don't think we would have thought how important our own immune system was as a driver of pathology in chronic diseases. And today we really realize that That inappropriate activation of our immune system and even just a slow burn, you know, inflammation has the word flame in it. It's, you know, it's associated with this burn and the redness and swelling, you know, that's where it came from. But this slow burn that's always kind of on all the time, that, as far as we can tell, there's nothing good about that. There's nothing positive about keeping the inflammatory signaling on all the time. So, so we think it really does represent a way to target some of these chronic diseases where we've, you know, we really have not had good ways to turn that, that, that mechanism off.

You see, I learned a lot about this already because I always, when they talked about inflammation and kind of the popular press parlance and, you know, on the website or whatever, I always am kind of picturing like, okay, it means I'm puffy on the inside, you know, that I am I'm somehow inflamed. I don't feel inflamed. But really what you're talking about is really a state of the immune system, which is emitting a signal that's saying something is wrong and causing a series of cellular responses that are manifesting at different levels that we're calling chronic inflammation. Does that sound about right?

That's exactly right. Yeah. And I think that it is, it has been challenging because You know, we use the same word for the acute and the chronic condition, but it's not exactly the same. You know, that you've activated this response, but it doesn't have a place to go and fight an infection or fight injury. It's kind of just a low-level persistent, you know, turning on of this immune response. And those cells are talking to each other constantly.

Yeah.

And they're saying, there's something wrong here. We just can't find where it is. And so it causes this heightened sense of activation. And like I said, as soon as those immune cells stay on, they're gonna find a— if they can't find a problem, they will create a problem. And that seems to be part of the problem with a lot of these diseases. Our own immune system is contributing to the pathology.

I see. So is it— so I don't know immunology very well, but I do know biology very well. And for every push, there's a pull. And that when you tend to have something on too often, you either detune the system to desensitize it to the persistent, in this case, inflammation. So is that really what we're looking at? Is that the immune system? So it's one of two things. Either the immune system is constantly on, so the body kind of pushes back against it, or is it the kind of thing that the immune system is always on and it pushes harder because it's not seeing the effect that it wants to see? Or I guess it could be both.

It could be both. Yeah. And I think that, that The challenge that we're starting to see is that the normal process of how the immune system gets activated in an acute setting is we have resident immune cells in our tissues. So our skin, for example, has a lot of immune cells and it makes sense because our skin is our barrier to the outside world. And so it's the largest tissue in our body, the largest organ system in our body, and it's constantly monitoring and looking what's going going on. And so there are professional cells that their whole goal is to look for specific signals and propagate the inflammatory response. That's their whole mission in life. And they're built to be around for a certain amount of time and they don't live forever. They have a pretty short lifespan. And that's by design because we want these pathways to turn off. What we're realizing is That cells can get reprogrammed that normally would not initiate these signals, but under the right conditions and under these reprogramming of their DNA at the epigenetic level, they actually allow these cells to start sending signals that they normally, you know, normal biology says these cells don't do that. But under the right conditions, they'll turn on this pathway. And those cells are long-lived cells. They're not cells that will die off and go away. And that's part of the resolution process. So if you get cells that aren't professional inflammatory inducers that suddenly take on this potential to turn on the inflammatory response, they stay around a whole lot longer and they continue to propagate these signals and they don't have the normal feedback loop that says, okay, it's time for this to go away. And so we're starting to realize that Some cells that have no business being involved in propagating these inflammatory responses turn these pathways on. And biology doesn't know what to do with that. It's like, okay, you know, I still see this signal, so something must be wrong here. And it kind of hijacks that whole system. So it's fascinating how this happens. And there's a lot of things that we're learning. For example, you know, the reason why I think that it's been really picked up, the idea of chronic inflammation has been picked up in the popular media and these dubious websites that have these nutritional supplements and things, is that there is a very strong connection between our metabolism and the activation of our immune system. And so, for example, we've learned a lot about how to activate certain types of cells with just using metabolic signals. So the immune system is very tuned to our metabolism and nutrients that are available to these cells. And when we have things like type 2 diabetes or obesity, even this metabolic syndrome, you're actually allowing the immune system to see nutrients that it really likes. Having a lot of glucose around, most immune cells are pretty tuned to They only use certain types of nutrients for energy. And if they see a lot of that, they'll just decide, oh, it's time to turn on this. So I think that there's a lot that we're learning about the combination of dysfunction at the cellular level plus dysfunction at the metabolic level. You know, that's kind of the magic for getting all of this process kicked off.

Oh, very cool. So we're speaking with David Beers. He's the CEO of Halea Therapeutics. We're talking about the biological and cellular basis of inflammation, its contribution to disease, and potentially some ways that his company is coming up with attenuating those processes. This is the Talking Biotech podcast by Calabria, and we'll be back in just a moment. In order to correct or possibly avoid different diseases. And so now that we know What this is, what have been the classical methods of controlling inflammation?

Yeah. So, I think the ones we're all familiar with are over-the-counter anti-inflammatories like Tylenol and Advil, ibuprofen and acetaminophen, and aspirin. Those are the ones that we think of. We call those nonsteroidal anti-inflammatories. The steroidal anti-inflammatories are corticosteroids that are immunosuppressive. And so, we've We've used, you know, inflammatory targeted drugs for a long time. And we've kind of had waves of discoveries. You know, the first were pretty immunosuppressive drugs. So we, you know, we figured out how to shut down the immune system, you know, and we use those drugs for like tissue or for transplant rejection. You know, when you transplant an organ, you want to stop the immune system from realizing that that's a foreign entity that you just put in your body. So we figured out pretty early we could turn the whole thing off. And we've been trying to figure out How do we get more specific and not block the whole immune system? And so there's been kind of waves of discoveries. We discovered, you know, aspirin's been around forever and we discovered, you know, not that long ago what it actually does. It inhibits enzymes called cyclooxygenases that are involved in producing signaling molecules that get released in the blood to tell the immune system, here's a problem. So it's a cascade. You know, there's initiating signals, and then those signals get propagated by other cells. And they, it's kind of like the telephone game, you know, it's like you tell the cell there's a problem, and the next one says there's a problem, and it gets propagated down the line. So we've figured out some of the signals along the line. And really, I think what's been the breakthrough, 20 years ago, we discovered that there's a signaling molecule at the very top of the chain that seems to be responsible for all the downstream things. And there's a few of them, actually a handful of them, but one of them is one called IL-1 beta, interleukin-1 beta. So IL-1 beta is a cytokine that seems to be one of these master triggers that when it's around, it starts telling the body, okay, let's get the troops organized and get them moving here. And it turns out IL-1 beta, so the regulation of IL-1 beta was not really well understood until about 20 years ago. So we discovered that IL-1 beta is produced as an inactive protein. So it's a protein that sits there in an inactive state and then something happens to activate it. And we discovered what that something was. It's a protease called caspase-1. So when you turn on caspase-1, it matures the pro-IL-1 beta to become an active IL-1 beta. And that's what gets released and causes all this. So we made that connection about 20 years ago to say there's this protease that's responsible for, you know, so there must be something that turns that protease on. And so that was the search for a while. It was like, what is it that turns this thing on? And it took us a while to actually figure it out. And the reason why is it's complicated. There's, as you can imagine, it's such a profound response in our body that the body and the cells in the body have a lot of regulation to make sure that this thing is controlled appropriately. And the thing that we discovered, what we call it, is the inflammasome. And there's actually multiple inflammasomes. I think we found about 5 of them, and there's probably more. But what an inflammasome is, is a multi-protein complex that gets assembled, that essentially its goal is to activate these proteases, caspase-1, and there's other ones that can be activated. But The one that we've studied the most, it's got, you know, science, we always come up with crazy names and, you know, they mean things and they're very complicated, but it's called the NLRP3 inflammasome. So that seemed to be, as we discovered the inflammasomes, we said, okay, it looks like we found the mechanism that activates these master cytokines. And You know, what do we know about this protein complex and how is it assembled? And just in the past few years, we figured out, you know, kind of, you know, we're still figuring it out. It's not a solved thing. We don't know how this whole thing gets regulated. But what we do know is this is a big protein complex. We know how it gets activated. We know how, you know, some of the components, the assembly and other proteins that are involved other than just NLRP3 itself. And then we started to ask, well, where is NLRP3? Where is it expressed? And what we discovered is every chronic disease, it gets turned on. So, you know, we looked at Alzheimer's, sure enough, it's there. We looked in, you know, cardiovascular disease, it's there. We looked at inflammatory bowel disease, it's there. You know, so we started looking, you know, all the way from the brain down to the skin on our toes. And it looks like every chronic inflammatory condition And this particular protein complex plays a role. And so, you know, as a drug developer, when you see something like that, it's like, all right, we got to target— that's the target. We got to turn this thing off and we got to figure out how to do it. So, you know, for the past few years, that's been kind of the focus of our company and my life is how do we turn this thing off? What's— how does it get turned on? As I mentioned, it's complicated. The process of turning it on is not straightforward.

Yeah.

So you can imagine turning it off is not easy, but we figured out a way to do it. And we're super excited about early days of what we're seeing, even in early clinical studies now in people, that it looks like this might be a real pathway to get after chronic inflammation in a way that we've never, never had before.

Well, you'd said there's 5 different inflammasomes, right? So if you target one, And you're able to control that one, does another one just kick in and compensate because biology's important and inflammation has a role?

Yeah, it's a great question. And genetically, we can ask that question. It's hard to study these things in animals because, you know, mostly we use rodents. We use mice and rats, and mouse immune systems are tuned a little differently than ours. We, you know, mice are very short-lived animals. They, an old mouse is 2 years old. I mean, most mouse— most mice in the wild don't live a year. So, so, you know, that's very different than us. Well, our immune system is built to keep us alive for a long time and to fight disease and, and injury for a long, long time. A mouse immune system is tuned to keeping them alive because they eat garbage all day long, right? I mean, that's— a mouse is living in, in garbage and eating garbage. And so its immune system is tuned a little bit differently than ours. If we ate what a mouse ate, it would kill us, right? So their immune system is built a little differently. And so it's been hard to sort all that out. But what we do know is that the other inflammasomes that we know get activated, they do play some role, but it looks like NLRP3 is the driver of chronic inflammation. And you talk about normal biology, chronic inflammation is not normal, right? And so I think that What we find, and we've kind of had to go through a little bit of a change in mindset of how we approach targeting this, because, you know, as it, once again, as a drug developer, when we find a target, we want to just hammer that target, turn it off, you know, say, okay, this enzyme is a bad enzyme. We're going to make sure it never is on ever. And when it comes to the immune system, that's probably not a good idea because NLRP3 has an important normal function. It just seems to be really associated with these chronic inflammatory signals. So how do we separate the good stuff from the bad stuff? And that's a real challenge. So I agree with you. If we put enough pressure on any of the biological system, there tends to be a loophole that these cells will figure out. Well, if I can't do it that way, I'll figure out a different way. And so I think that the mindset of chronic inflammation, I think, is a little different That instead of trying to develop a drug that we take every day for the rest of our life, it's almost, you know, let's just keep pushing the reset button and let this thing turn off and wait for it to turn on again and then turn it off again. So kind of how we use over-the-counter anti-inflammatories, you know, we take them when we feel bad and we don't take them every day. Well, some people do. Not highly recommended, but, you know, We kind of take them when we feel things flaring up, and maybe that actually is the right approach for these chronic inflammatory conditions. Instead of just keeping pressure on where you're pushing biology to get around what you're doing, you just go in and say, I'm just going to reset this. So that's kind of the approach that we're thinking about and what we're working on now.

Well, that's a pretty interesting concept. And so is there some sort of a biomarker or a test that you would do at home or maybe in a physician's office that would tell you, hey, today's a good day that you might want to take this thing? You know, you had too many tequila shots last night and you're, you know, you're leaking cytokines. You know, give me a— like, what do you do?

It's a double-edged sword for us because the cool thing is most of these signals get secreted into the blood. And so, you can actually watch things change. You know, I could inject something into you that would cause an inflammatory response and I could watch it happen. Like, I could see the cytokines and chemokines change very rapidly. The problem is that, you know, the normal wear and tear of our day, these things go up and down. In fact, they go up and down when we're asleep and when, you know, when we, you know, it's, you know, intuitively, you know this because, you know, when you're sick at nighttime, you get a fever. You don't have a fever during the day, you have it at night. Why is that? Well, these hormones go up and down naturally during the day. So, they're high at certain times and they go down. And so, you know, our immune system responds to that. So it's been challenging to find great biomarkers. We have a few, and one of them that actually we discovered and actually developed as a biomarker for cardiovascular inflammation is a protein called C-reactive protein. That seems to be the most well-validated measure of your systemic inflammatory condition. So if you have a chronic inflammatory condition and your immune system's ramped up, C-reactive protein's produced in your liver. You have cytokines that turn it on and it'll go up. And, you know, most people should have almost undetectable, really, really low C-reactive protein. And if you have measurable, and some people have very, very high C-reactive protein, it gives you a sense of what's going on in your immune system. And there's a few other markers that have been pretty well validated. We're getting better and better with technology. And I think, you know, one of the things that we're excited about is that we can actually take individual cells from your blood and profile what those cells are doing. And that tends to give us, I think, a better picture. So we're using some new technology that allows us to do single-cell proteomic analysis to say, what is it that they, you know, so I can take a monocyte out of your blood, you know, And one cell at a time say, what do these monocytes look like? What do these neutrophils look like? And it gives us a pattern to say, this is what a chronic inflammatory condition looks like and here's what normal looks like. And so we use that and we're getting better at this all the time, but there's still, it's still in early days and trying to establish a bona fide kind of universal set of markers that we can look at that tell us the drug is working or that we're turning off this pathway and when it's ramped up. I mean, I think we're pretty good at when things are terrible, we can see that, but can we move people from this chronically inflamed state that this kind of slow burn, can we turn that off? And I think we're getting there and I think we're You know, as we get new drugs that target these pathways, it opens up possibilities of being better at monitoring this. But absolutely, that's the goal. And, you know, we want to incorporate these types of measures as people get their yearly physicals and have this blood work. They get a sense of, you know, an inflammatory score, you know, that you were 2 and now you're 10. And, you know, we need to change that.

Well, thus far, just looking at the website, The star of the show at this point is something called HT-6184. And aside from the clever name, what is it and how does it work?

Yeah, we always get some guff about how we name things. And when it's early on, you just name them by numbers. But actually, we will in August, we'll be able to tell you the real name of this drug. Every drug A real drug will have a generic name. And, we just got notice that we'll be able to release the generic name. So, we'll have a fancy name after that, but we call it HC-6184. So, we discovered this in a really interesting way. So, I love human genetics. So, I think that we learn a lot about biology from when biology gets messed up in people. So, you can see You know, that a human experiment tells you a lot about, you know, what goes wrong even at the cellular level. So we've— one of our co-founders actually was involved in the discovery of a genetic risk factor for Alzheimer's disease. And this is a protein called ApoE. And it turns out if you have the ApoE4 polymorphism, and you can actually screen this now with 23andMe and Ancestry and all these DNA sequencing, these direct-to-consumer DNA sequencing, you can actually figure out whether you have this. It turns out the actor Chris Hemsworth, the Thor guy from the Marvel movies, he has APOE4. And he publicly came out and said, I discovered I have this and my risk for developing Alzheimer's is very high compared to the general population. And so, If you have one copy of APOE4, your risk for Alzheimer's is 3 times the general population. If you have 2 copies, it's as much as 12 times, it's 10 to 12 times, you know, so you have a much higher risk. So the question is why? What does APOE4 do? And so, you know, our co-founder, Dr. Kawai, Keoni Kawai, he and I have been working on this for a few years. So we discovered a family in Utah. So our company's in Utah. Utah is a great place to do human genetics. We have big families and we have a resource here in Utah that most people don't have. And most, in fact, no other state has this. So the Mormon Church has developed a genealogical database that tracks families. And we actually took that database and merged the public health records into that database. So you can ask questions in Utah, like show me a family that has Alzheimer's in 4 generations and it'll pull that right up. So it's an incredibly powerful tool for doing human genetic studies. So we found a family in Utah that has the APOA4 polymorphism, has multiple generations alive. And interestingly, when we studied this family, nobody in the family, very few people in this family had signs of Alzheimer's. So that's very unusual for having a high-risk genetic predisposition and nobody has it. There's something else going on with these people. So we actually sequenced over 200 family members, their whole genome, And asked, do they have differences or polymorphisms that are unusual, rare variants that may be modifiers of this risk factor? And we discovered something and we published that and it's called, we found a rare variant of a gene called RAB10. And then we connected the dots between RAB10 and say, well, what does RAB10 do? Well, RAB10 is part of protein trafficking inside the cell. It's kind of the shipping master that tells the proteins where to go inside the cell. And it sits in a place called the Golgi network inside the cell that kind of is responsible for packaging proteins and pushing them to different places inside the cell. It turns out that if you have reduced RAB10 function, you have reduced ability to package certain proteins. And it turns out NLRP3 is one of those proteins. So we discovered that if you have a loss of function of RAB10, you have a decreased ability to respond to inflammatory signals. And when you study this family, they actually had resilience, not just to Alzheimer's, but it looks like they probably have less cancer and less heart disease and they live longer. So that's all good stuff. So we said, well, let's make a drug out of that. Let's find out how do we target that? And so It turns out RAB10 is a challenging protein to try to develop a drug against. So we found a way to target upstream things that turn on RAB10 and then downstream things that are involved in the assembly of the inflammasome. And so 6184, HT6184, actually disrupts the formation of the inflammasome and does it by blocking the interaction of NLRP3 with another protein called NEX7. And we're the first company to try this. We developed— we discovered this drug as a, what we call it, an allosteric modifier or an allosteric modulator of NEX7 function. So it blocks the ability of NEX7 to bind to NLRP3, which is a critical component of the assembly of the inflammasome. So essentially what we do is we block the assembly of this protein complex that is involved in activating the very first step in chronic inflammation. And by doing that, all the downstream stuff gets turned off as well. So it's pretty exciting. You can see what happens in the cell is we can take, we can tell immune cells there's a problem and they get really ramped up. We treat with our drug and they don't respond at all to those signals. So it's really, really exciting. We're, we, you know, we, we've treated many different models of, of every inflammatory condition you can think of from arthritis to Alzheimer's to chronic inflammatory bowel diseases to psoriasis, and every single one of them respond to turning off this pathway. So we think it's got a lot of potential to treat a lot of different conditions. And we're just actively trying to show that this actually translates into real people and it really works in these chronic conditions.

Well, correct me if I'm wrong, but it would seem like this would be a huge one for things like rheumatoid arthritis and lupus and other autoimmune Absolutely.

And, and, you know, we've got really, really nice data to show that, uh, in, in a, in a way that is different than any other, you know, approach that we've taken. And a lot of these, a lot of these conditions like arthritis, rheumatoid arthritis, for example, we have a lot of drugs to treat it, but, but most of those drugs are long-acting antibodies that, that kind of take out one of the signaling molecules. So, Humira is probably one that everybody's heard because they've TV commercials all the time for Humira. And yeah, they've got the ask your doctor if Humira is right for me thing. So what Humira does is it, it blocks one of the downstream. So it's, it's actually right downstream of the inflammasome. So IL-1 beta turns on a protein called TNF-alpha and Humira binds to TNF-alpha. So these long-acting biologic drugs have been kind of our first approach for We call them anti-cytokines. They take out these signals. What's different about what we're doing is we turn off the source of the signal. It goes away. And what's exciting is that, as I mentioned, we don't have to keep our drug around all the time to see an effect. We can just push the reset button and say, that complex needs to go away. It goes away and all that downstream stuff turns off. And so the question is, you know, Can we dose in a way? And by the way, if you pay attention to those Humira commercials, there's a lot of warnings of using those drugs. And most of those warnings are associated with this could suppress your immune system. Don't take this if you have tuberculosis or some other active infection because it will— your immune system, you'll stop the ability of your immune system to fight that. All of that's bad, right? I mean, we think that this approach is really interesting because if this protein complex is what's constantly sending out the signal and we can make that complex fall apart and go away, then we don't have to keep the pressure on. So if you do get a bacterial infection, you can respond normally because our drug is gone. It did what it was supposed to do and it goes away. You know, so we think it's like it could be a paradigm shift for the way that we treat these chronic conditions that does not compromise the acute immune response or the innate immune response, which is Which is what we've had problems with, you know, with all the other drugs that are out there.

Well, another drug that's in your pipeline is something called HT4253. And should I ask my doctor if HT4253 is right for me?

How is it?

What is this? And how is this one different?

Yeah. So it is our second way of turning off this pathway. And so So we discovered through this human genetic experiment that RAB10 is important in the first step of assembling the inflammasome. What HT4253 does is it stops the activation of RAB10. So 6184 stops downstream of RAB10. 4253 actually stops upstream of RAB10. So we kind of have 2 ways of going about it. And what's different about 4253 is it gets into the brain really, really well. So one of the challenges of developing drugs is we have something called the blood-brain barrier, and it's there for a good reason. We don't like transporting potentially dangerous things into our brain. Our body protects our brain kind of at all costs. And so getting stuff to get into the brain is not trivial. And it turns out 4253 has a really good ability to get into the brain. And so we decided we're going to use that. As our first approach to try to go after neuroinflammation. So those are our 2 different, you know, different same pathway, different mechanisms. One for the brain, the rest, you know, the other one for the rest of the body.

Oh, very cool. That's, but it's just similar, but the same mechanism still inhibiting that inflammasome. That's really cool. So where do both of these drugs stand in terms of clinical trials?

Yeah, so we, um, I HD-6184 was our first drug into the clinic as a company, and we've completed now a phase 1 study, which is a— we did a healthy volunteer study. So we just took healthy people. And in phase 1, we typically just try to figure out, you know, can we give this drug over either a single dose or multiple doses, and does it do bad things to people? And we showed that it looked really good. We didn't see any real You know, strong, no signals of toxicity. And so then we moved into 3 different phase 2 clinical trials. And so we're doing those studies right now. One of those is in a rare bone marrow condition called myelodysplastic syndrome. Turns out if you get inflammation in your bone marrow, it does bad things to your ability to make blood. And so we're treating patients that, and we have, we're actively enrolling patients and it's moving along really well. We like it because it's actually something we can sample easily. We can take bone marrow biopsies, we can measure what's going on in the blood. So that was our first one. And then we just completed a phase 2 study in post-procedural inflammation. So after a surgery, you can cause damage and you will trigger an inflammatory response and it's a systemic response. Your whole body, you know, responds to it. So we want to see if we could attenuate that response. And then the third study, is in a rheumatoid arthritis study. And so those are going on and we're actively ramping things up. We got a couple more in the hopper coming along and we're pretty excited about the potential what this could do in a lot of places. And just kind of a teaser out there, you know, we think that this plays a role in metabolic diseases like type 2 diabetes and obesity even. And, you know, you can, you know very well, everybody knows that the You know, GLP-1 drugs have been really remarkable in weight loss and in treating obesity. We think there's a component of targeting inflammation at the same time with these drugs that could be really exciting. And so hopefully in the next, you know, few weeks or months, we'll have some information we can put out there what our drug does in that context. So exciting times. The other, 4253, is just getting ready now to go into the first patients. And so we're We're just getting all the regulatory documentation done and we should be able to announce here very soon that we treated the first patient with 4-2-5-3.

Yeah, this is a really fun interview for me because this is something that I knew very little about coming in, but it fits like a puzzle piece with what I did know and it fills all the gaps because having some working knowledge on these different types of diseases and the role that inflammation may play, this makes total sense. So, what's the timeline look like on these things? Are we looking at 10 years, 5 years if everything goes perfectly well, or is that something that your crystal ball isn't tuned to show?

Yeah. So, it's always a challenge making forward-looking statements and you have to always be careful about—

That's right.

But, in our world, You know what we we can't just go right to market, right? It's a very heavily regulated industry, and so there's a lot of hurdles we have to go through. But you know, if we see strong signals, you know, I I think there's motivation by everybody. Every stakeholder wants to to develop drugs to target chronic diseases. It's it's it's a huge issue for us. I think that most people don't realize how old our population is getting in the old days. You know, which was when we were kids, you know, there were a lot more young people than there were old people. And, you know, so we kind of had a pyramid-shaped demographic. And today it's more like a column. There's just as many elder people, older people as there are younger people. And pretty soon it's going to be an upside-down pyramid where there's going to be old, more old people than there are young people. And the problem with that is chronic conditions follow age. And in fact, inflammation follows age as well. We are more sensitive to inflammatory signals as we get older. So we think that there's, you know, that there's a revolution that we're just at the beginning of, of moving away from sick care, which is kind of what we've done, not really healthcare. We're not trying to keep people healthy. We're treating people that are sick to really trying to keep people healthy. And there's a lot of motivation from everybody to say, if we can keep people healthier longer, that's good for everything, for all, you know, not just the individuals, but for our economies, our countries. And if we're going to be living longer, we should be living longer healthy, right? I don't think any of us looks forward to being, you know, the last 10 years of our life being in a long-term care facility. That's no fun for anybody. And economically, it's a disaster. So, you know, our goal is if we could add one more healthy year to your life, What impact could that make in the world? A huge, huge impact, right? So we think that we can, you know, we're excited about working with the FDA and other regulatory agencies around the world to say, how can we do this so it's not going to be 10 years from now? Is there a path to get this approved quicker and to get this to people so that we can start making a difference in people's lives? Because we really think that that's the potential is Let's change our mindset and quit waiting for people to get sick to treat them and intervene when we have the slow burn before it starts to become the fire that's burning down the building. Let's take care of it early on. And I think that there's a lot of movement towards that direction. And to be honest, the GLP-1 drugs are really changing a lot of that mindset. They're like, wait a minute, we can change the trajectory of people's health over their life by intervening with some of these, these new biological pathways that we've discovered. So hopefully that's the, that's the road that we can be on. And—

That's super exciting. I mean, even if you add a little bit to lifespan, adding more to healthspan really is where we need to be these days because we're, we're living older and older, but, you know, not always healthier and healthier. And I think that this is a Good potential in solving that problem. Well, David Beers, thank you very much for being a guest today. I really appreciate it. And as the breakthroughs continue to roll out and the approvals happen, I really hope you get in touch with me again and we'll update the audience on where things stand because this is a really exciting and novel area in which you have the opportunity to solve some really interesting problems that are affecting many people. So thank you very much for joining me.

No, it's been my pleasure. And I will— I'll come back anytime and let you know what's going on.

Very good. And then for the listeners, thank you very much for listening to the Talking Biotech podcast. Take a look at what's happening at Halea Therapeutics online and listen to this podcast for updates. Since inflammation seems to play such an important role in many different diseases and such a broad spectrum of different disorders, that being able to control it may have very important implications in our long-term health. So, Keep an eyeball on this particular area. Thank you so much for listening to the Talking Biotech podcast, and we'll talk to you again next week.