Oxidized Cholesterol and Cardiovascular Innovation

I first learned about the problem of oxidized cholesterol, which is most of what I'm going to talk to you about today, from Aubrey even before the events that he's just talking about back when I was a graduate student. He came to speak at my university and actually gave a couple lectures on a couple of different topics in some different universities and departments around the area and I followed him around a little bit and one of the things that that he taught me about was this idea of oxidized cholesterol that when a free radical, an oxygen free radical, bumps into regular cholesterol and It more often than not turns into 7-keto-cholesterol, which is very toxic and involved in multiple aspects of aging. And I'm going to talk almost exclusively today about the cardiovascular disease atherosclerosis, which is what we've been focusing on in trying to bring our first drug to clinic. But what I want to emphasize is that this is a basic mechanism of aging, one of the basic kinds of damage that accumulates with age in various cells and tissues. And so the mechanism, the model that we have for atherosclerosis, which is the thickening and the clogging of the arteries, is that macrophages their job is to eat. And in atherosclerosis, they go to the site of a lesion, and their job is to eat up the junk that they find there. And they're very good at their job. But when they eat up too much of the lipids and other junk that they find, they start eating up a little bit of 7-keto cholesterol, 7-KC. And just a little bit of that, once you get enough of it over time... enough to shut down the lysosomes of the macrophage, which is the garbage processing unit of the cell, and the macrophage then can't metabolize really much of anything anymore, and not the lipids, and they balloon up, they keep eating, and they balloon up into something called the foam cell. The foam cell layer of the plaque is a fundamental step in the progression of plaque. And our goal was to see if we could get rid of the 7KC and thereby rejuvenate the macrophage and see if we could put it back to work doing what it's supposed to do. I'll just take a little bit of an interlude to talk about how people have been treating cardiovascular disease and developing therapies. There's drugs for trying to reduce the likelihood of having a cardiovascular event, like blood thinners. Then the next generation of drugs is lipid-lowering therapies, which, you know, now we're going on about three, a third decade of those. Then the next generation of lipid-lowering therapies, which are better at lowering lipids, but not really doing anything fundamentally different. Now we're actually starting, right now what's starting to come out is the anti-inflammatories, which I think are starting to address some of the actual damage problems that are going on and some of the genetic problems, so things like LP little a. But now I want to push us into real damage reversal therapies, and that's why we're targeting 7KC in cardiovascular disease. And just a little bit. You're starting to see some good quality clinical data come out about association of 7KC with cardiovascular disease. Not the same level, so there's maybe three good decent sized studies of 7KC and cardiovascular disease as opposed to say like a thousand with LDL. But I think the association not just with correlating with disease, but also risk association that the more 7KC you have, the worse off you are. Makes me think that we're in a good position and at a good time in history to finally, almost maybe 20 years after I learned about 7KC, to actually be doing something about it. So back at the... Foundation, like Aubrey was mentioning at the beginning, we were working on a lot of fancy enzyme engineering approaches that were cool, but I started thinking, trying to think of ways that I could drive something to clinic really fast. And so I dug into the literature and found these molecules called cyclodextrins. Cyclodextrins are cyclic carbohydrates and there was a lot of work back in the 80s and 90s that we're looking at the cholesterol and oxidized cholesterol binding properties of cyclodextrins. So we started playing around with them there at the foundation, got some assays working and and then started modeling them computationally. And I didn't bring any of the computational data with me today, but the earliest modeling that we did showed that the best binding of 7KC happened when you took two medium-sized cyclodextrins, beta cyclodextrins, together in a head-to-head configuration, and that was the most stable complex. And so once we started getting things working, we asked ourselves, well, if that's sort of the natural way that these things come together, what if instead of taking old, decades-old cyclodextrins off the shelf and playing around with them at very weak potency the way most people do with cyclodextrins, what if we built new ones? And what if we stuck them together and dimerized them the way, and, you know, and just forced them to emphasize that confirmation? And Long story short, we did that and it worked exceedingly well. And we were able to invent new cyclodextrins that were about a thousand times more potent than the stuff you could get out of the chemical catalog. And we could engineer them for high specificity for the... for a 7KC over regular cholesterol. And that turns out to be really important for making them efficacious, but also safe. We can make a lot of cyclodextrins. We have a lot of prototypes on the shelf that are very potent, but bind cholesterol really well, and they're all really toxic. If you strip too much cholesterol out of a cell, that cell falls apart instantly. and you'll get toxicity from that. So we carefully engineered our Cyclodextrin to have a strong preference for 7KC. And then we did what we set out to do, which was try them in foam cells. So we took some macrophages and grew them on a plate and then gave them just a little bit of 7KC that you can see in the bottom. group of cells there. And you see that red sort of blotchy droplets in the middle, they're called lipid droplets. That happens really quickly when you give them just a little bit of 7KC. And then when we give them our drug, they quickly go back to looking normal. And they don't just look normal, they start behaving better again. So we can take macrophages, we can take mouse macrophages, we can take human macrophages. We can treat them with 7KC, we can treat them with oxLDL, and we see the same kind of phenomenon that I'm showing here, just a few examples of. They not only look better, but they start acting the way they should act. The job of a macrophage is to eat. They eat less when they are poisoned with 7KC and they turn into foam cells, and their activity comes back when you reverse. that with our lead drug, which we call UDP003. I'm not going to go into the massive amount of profiling that we've done on these cells too much, but I just put in a couple of examples of some gene expression profiling that we've done to look at some key pathways in lipid metabolism that get shut off. when the cells become foam cells and get turned back on when we rescue with our drug. And then another thing that happens is that macrophages turn on a signal that says, don't eat me, the same way some cancers do to resist the immune system. And another... company is trying to target this particular cell surface receptor to target atherosclerosis. And so they're targeting this CD47 gene in particular. And so we wanted to know whether we were also affecting that. And we are indeed able to at least bring that down to close to normal levels again. Alright. And one more thing, some brand new data that I think you guys are going to hear about first here is that we've been profiling the inflammatory cytokine profile that macrophages give off when they are normal or when they're foam cells and then when we rescue them. And this is just two of the most dramatic examples that we've found so far, is that IL-8 and MIP1-alpha pro-inflammatory cytokines get super hyperactivated. So this is actually fold activation, not percent increase. And so these are the two most dramatic examples we've found, is that IL-8 is getting over 25 times upregulated when they turn into foam cells, and then we're rescuing that by a pretty remarkable amount with a very short-term treatment with our drug. So that's the main bit of the science that I wanted to focus on today. And what's most exciting is that we're not just an R&D company anymore. We're transitioning into being a clinical stage company. And we're getting ready to enter clinical trials, hopefully later this summer. So this is our clinical trial plan. In our overall clinical trial plan, I'll go into a little bit more detail about these different, at least the first two steps in the next couple of slides. We're moving, we're going to do our phase one in Australia in Adelaide and it's going to be primarily a safety trial and we'll be able to look at some biomarkers and some patients. And that will lead directly into a phase two trial where we'll look at a much larger number of patients looking directly at efficacy on coronary artery disease of the plaque. And so non-invasive imaging of atherosclerotic plaque has really advanced in leaps and bounds just in the last five to ten years. So we're going to have some fantastic opportunity. to look and see whether we can actually regress plaque in humans in just the next few years. And then if we can, there's lots of indications that are open to us to go into for approval. So we can go for a smaller indication like peripheral artery disease, or we can look at chest pain, angina, or we can go for the biggest type of indication that... that we can imagine, which would be like full coronary artery disease with looking at reducing numbers of heart attacks and strokes. So that's our strategy. We have, importantly, to get here, we had to make an actual drug product, and that's way beyond Utah talked a little bit about some of the challenges and how important it is, but I think he underplayed a little bit how challenging and time-consuming and expensive it is to take a drug, whether it's a cell or gene therapy product, or a small molecule drug, or kind of a medium molecule like our drug, and manufacture it at high quality at high scale that is safe for people. So we managed to scale our manufacturing to the kilogram scale and create a liquid formulation. And now it's ready in single-use vials, sterile individual-use vials for patients. We have our first CGMP batch done. We've had many interactions with regulators. We've met with regulators in the UK. We've had our pre-IND meeting in the US. And this week, we're submitting... in the next few days, end of this week or beginning of next week, our clinical trial application in Australia, just putting the final edits on the protocol. And we finished all of the GLP safety studies, so all of the small and large animal testing is done, our drug is safe, and it's ready for people in phase one. So we've got some phenomenal, we've brought, we've really reached into the, you know, like Aubrey said, I come really strongly from the aging field. I only worked on aging when I was an academic and I went into the foundation and of course only worked on aging when I was at the Aging Research Foundation and now we're spinning out a company and we're focusing on cardiovascular disease. So that's been a learning curve and part of that has been bringing on some top cardiologists to advise us. And these are some of the biggest names in cardiology. And most importantly, that first one, Steve Nichols, is the biggest cardiologist in Australia. And bringing him on board really opened up doors for us in Australia, helped us get introduced to people that we needed to know to make the clinical trial happen quickly. to get to work with the best people. And he's co-directing our phase one, which for the kind of guy who usually gets called to oversee the phase threes by the giant pharma companies, we're really lucky to have somebody like him helping run our phase one. So a little bit of detail about our phase one. It's going to have 72 healthy volunteers. And as soon as that's done, we'll get to work on actual patients. And so we'll be recruiting 12 patients with coronary artery disease to participate in what you could call a Phase 1B portion of our Phase 1 clinical trial. That's all planned out, and like I said, hopefully starting within two months here, maybe six weeks. The phase two is a bit more conceptual. Tentatively we're looking at the same patient pool as in the 1B, the same indication group, but expanding to 150 patients at a placebo and a low-dose and a high-dose group, and tentatively flagshiping that at Cedars-Sinai in Los Angeles. And so that trial will begin. hopefully in something like a year and a half, and to be finishing up by around the end of 2027, beginning of 2028. And if that succeeds, that will be our, let's call it our chat GPT moment. If we're able to see patients with their arteries, their coronary arteries, you know, half or 80% occluded, and have that drop way down, you know, below 50% occluded, that will blow the lid off of this. That will be when, you know, the bidding wars start from the big pharma companies when everybody sits up and takes notice and realizes that you can target a basic aspect of aging and reverse a fundamental disease of aging. And that's the moment that we're really looking forward to. So just a little bit before I finish up on other applications for our drug, we're doing some small R&D projects on stroke recovery and Alzheimer's disease and some orphan disease. And we're also interested in applying our technology, this cyclodextrin technology and the cyclodextrin dimer technology, to other disease targets. Things like these retinoids that accumulate in the eye, causing macular degeneration, other oxysterols, and other targets as well. And our technology is also applicable to things that aren't in aging. So, of course, it's technology, and so we think it could be valuable for overdose reversal, so for... you know, for anti-skin rash stuff, like things like poison ivy, things like that. We're really hoping to be partnering with experts in other fields, and we're starting to have experts in those fields call us and say, can we use your technology for our problems? And we're really looking for partners and partnerships in those realms. And we're also looking for other ideas of things that we can target. ideally things that are relatively small and hydrophobic. So things that are, say, a thousand or fewer Daltons in size and ideally hydrophobic that we can target with our technology. We have this powerful computational platform that we've built where we can take any target and throw it in and model cyclodections and make predictions about new ones that we can bind. with them. So give us your ideas and we'll try them and we have a new AI training algorithm that we're training using thousands of simulations that we've already performed that we hope to be able to use so that it doesn't have to be humans anymore coming up with the ideas for the structures of the drugs. We just plug in the target and ask the algorithm to tell us what the best drug to make and then we can make a prototype and try it out.

But what I want to emphasize is that this is a basic mechanism of aging, one of the basic kinds of damage that accumulates with age in various cells and tissues. And so the mechanism, the model that we have for atherosclerosis, which is the thickening and the clogging of the arteries, is that macrophages their job is to eat. And in atherosclerosis, they go to the site of a lesion, and their job is to eat up the junk that they find there.

And they're very good at their job. But when they eat up too much of the lipids and other junk that they find, they start eating up a little bit of 7-keto cholesterol, 7-KC. And just a little bit of that, once you get enough of it over time...

enough to shut down the lysosomes of the macrophage, which is the garbage processing unit of the cell, and the macrophage then can't metabolize really much of anything anymore, and not the lipids, and they balloon up, they keep eating, and they balloon up into something called the foam cell. The foam cell layer of the plaque is a fundamental step in the progression of plaque. And our goal was to see if we could get rid of the 7KC and thereby rejuvenate the macrophage and see if we could put it back to work doing what it's supposed to do.

I'll just take a little bit of an interlude to talk about how people have been treating cardiovascular disease and developing therapies. There's drugs for trying to reduce the likelihood of having a cardiovascular event, like blood thinners. Then the next generation of drugs is lipid-lowering therapies, which, you know, now we're going on about three, a third decade of those.

Then the next generation of lipid-lowering therapies, which are better at lowering lipids, but not really doing anything fundamentally different. Now we're actually starting, right now what's starting to come out is the anti-inflammatories, which I think are starting to address some of the actual damage problems that are going on and some of the genetic problems, so things like LP little a. But now I want to push us into real damage reversal therapies, and that's why we're targeting 7KC in cardiovascular disease. And just a little bit. You're starting to see some good quality clinical data come out about association of 7KC with cardiovascular disease.

Not the same level, so there's maybe three good decent sized studies of 7KC and cardiovascular disease as opposed to say like a thousand with LDL. But I think the association not just with correlating with disease, but also risk association that the more 7KC you have, the worse off you are. Makes me think that we're in a good position and at a good time in history to finally, almost maybe 20 years after I learned about 7KC, to actually be doing something about it. So back at the...

Foundation, like Aubrey was mentioning at the beginning, we were working on a lot of fancy enzyme engineering approaches that were cool, but I started thinking, trying to think of ways that I could drive something to clinic really fast. And so I dug into the literature and found these molecules called cyclodextrins. Cyclodextrins are cyclic carbohydrates and there was a lot of work back in the 80s and 90s that we're looking at the cholesterol and oxidized cholesterol binding properties of cyclodextrins.

So we started playing around with them there at the foundation, got some assays working and and then started modeling them computationally. And I didn't bring any of the computational data with me today, but the earliest modeling that we did showed that the best binding of 7KC happened when you took two medium-sized cyclodextrins, beta cyclodextrins, together in a head-to-head configuration, and that was the most stable complex. And so once we started getting things working, we asked ourselves, well, if that's sort of the natural way that these things come together, what if instead of taking old, decades-old cyclodextrins off the shelf and playing around with them at very weak potency the way most people do with cyclodextrins, what if we built new ones? And what if we stuck them together and dimerized them the way, and, you know, and just forced them to emphasize that confirmation?

And Long story short, we did that and it worked exceedingly well. And we were able to invent new cyclodextrins that were about a thousand times more potent than the stuff you could get out of the chemical catalog. And we could engineer them for high specificity for the...

for a 7KC over regular cholesterol. And that turns out to be really important for making them efficacious, but also safe. We can make a lot of cyclodextrins. We have a lot of prototypes on the shelf that are very potent, but bind cholesterol really well, and they're all really toxic.

If you strip too much cholesterol out of a cell, that cell falls apart instantly. and you'll get toxicity from that. So we carefully engineered our Cyclodextrin to have a strong preference for 7KC. And then we did what we set out to do, which was try them in foam cells.

So we took some macrophages and grew them on a plate and then gave them just a little bit of 7KC that you can see in the bottom. group of cells there. And you see that red sort of blotchy droplets in the middle, they're called lipid droplets. That happens really quickly when you give them just a little bit of 7KC. And then when we give them our drug, they quickly go back to looking normal.

And they don't just look normal, they start behaving better again. So we can take macrophages, we can take mouse macrophages, we can take human macrophages. We can treat them with 7KC, we can treat them with oxLDL, and we see the same kind of phenomenon that I'm showing here, just a few examples of. They not only look better, but they start acting the way they should act.

The job of a macrophage is to eat. They eat less when they are poisoned with 7KC and they turn into foam cells, and their activity comes back when you reverse. that with our lead drug, which we call UDP003. I'm not going to go into the massive amount of profiling that we've done on these cells too much, but I just put in a couple of examples of some gene expression profiling that we've done to look at some key pathways in lipid metabolism that get shut off. when the cells become foam cells and get turned back on when we rescue with our drug.

And then another thing that happens is that macrophages turn on a signal that says, don't eat me, the same way some cancers do to resist the immune system. And another... company is trying to target this particular cell surface receptor to target atherosclerosis. And so they're targeting this CD47 gene in particular.

And so we wanted to know whether we were also affecting that. And we are indeed able to at least bring that down to close to normal levels again. Alright. And one more thing, some brand new data that I think you guys are going to hear about first here is that we've been profiling the inflammatory cytokine profile that macrophages give off when they are normal or when they're foam cells and then when we rescue them. And this is just two of the most dramatic examples that we've found so far, is that IL-8 and MIP1-alpha pro-inflammatory cytokines get super hyperactivated.

So this is actually fold activation, not percent increase. And so these are the two most dramatic examples we've found, is that IL-8 is getting over 25 times upregulated when they turn into foam cells, and then we're rescuing that by a pretty remarkable amount with a very short-term treatment with our drug. So that's the main bit of the science that I wanted to focus on today. And what's most exciting is that we're not just an R&D company anymore. We're transitioning into being a clinical stage company.

And we're getting ready to enter clinical trials, hopefully later this summer. So this is our clinical trial plan. In our overall clinical trial plan, I'll go into a little bit more detail about these different, at least the first two steps in the next couple of slides. We're moving, we're going to do our phase one in Australia in Adelaide and it's going to be primarily a safety trial and we'll be able to look at some biomarkers and some patients.

And that will lead directly into a phase two trial where we'll look at a much larger number of patients looking directly at efficacy on coronary artery disease of the plaque. And so non-invasive imaging of atherosclerotic plaque has really advanced in leaps and bounds just in the last five to ten years. So we're going to have some fantastic opportunity.

to look and see whether we can actually regress plaque in humans in just the next few years. And then if we can, there's lots of indications that are open to us to go into for approval. So we can go for a smaller indication like peripheral artery disease, or we can look at chest pain, angina, or we can go for the biggest type of indication that...

that we can imagine, which would be like full coronary artery disease with looking at reducing numbers of heart attacks and strokes. So that's our strategy. We have, importantly, to get here, we had to make an actual drug product, and that's way beyond Utah talked a little bit about some of the challenges and how important it is, but I think he underplayed a little bit how challenging and time-consuming and expensive it is to take a drug, whether it's a cell or gene therapy product, or a small molecule drug, or kind of a medium molecule like our drug, and manufacture it at high quality at high scale that is safe for people. So we managed to scale our manufacturing to the kilogram scale and create a liquid formulation. And now it's ready in single-use vials, sterile individual-use vials for patients.

We have our first CGMP batch done. We've had many interactions with regulators. We've met with regulators in the UK.

We've had our pre-IND meeting in the US. And this week, we're submitting... in the next few days, end of this week or beginning of next week, our clinical trial application in Australia, just putting the final edits on the protocol. And we finished all of the GLP safety studies, so all of the small and large animal testing is done, our drug is safe, and it's ready for people in phase one. So we've got some phenomenal, we've brought, we've really reached into the, you know, like Aubrey said, I come really strongly from the aging field.

I only worked on aging when I was an academic and I went into the foundation and of course only worked on aging when I was at the Aging Research Foundation and now we're spinning out a company and we're focusing on cardiovascular disease. So that's been a learning curve and part of that has been bringing on some top cardiologists to advise us. And these are some of the biggest names in cardiology. And most importantly, that first one, Steve Nichols, is the biggest cardiologist in Australia.

And bringing him on board really opened up doors for us in Australia, helped us get introduced to people that we needed to know to make the clinical trial happen quickly. to get to work with the best people. And he's co-directing our phase one, which for the kind of guy who usually gets called to oversee the phase threes by the giant pharma companies, we're really lucky to have somebody like him helping run our phase one.

So a little bit of detail about our phase one. It's going to have 72 healthy volunteers. And as soon as that's done, we'll get to work on actual patients. And so we'll be recruiting 12 patients with coronary artery disease to participate in what you could call a Phase 1B portion of our Phase 1 clinical trial. That's all planned out, and like I said, hopefully starting within two months here, maybe six weeks.

The phase two is a bit more conceptual. Tentatively we're looking at the same patient pool as in the 1B, the same indication group, but expanding to 150 patients at a placebo and a low-dose and a high-dose group, and tentatively flagshiping that at Cedars-Sinai in Los Angeles. And so that trial will begin. hopefully in something like a year and a half, and to be finishing up by around the end of 2027, beginning of 2028. And if that succeeds, that will be our, let's call it our chat GPT moment.

If we're able to see patients with their arteries, their coronary arteries, you know, half or 80% occluded, and have that drop way down, you know, below 50% occluded, that will blow the lid off of this. That will be when, you know, the bidding wars start from the big pharma companies when everybody sits up and takes notice and realizes that you can target a basic aspect of aging and reverse a fundamental disease of aging. And that's the moment that we're really looking forward to.

So just a little bit before I finish up on other applications for our drug, we're doing some small R&D projects on stroke recovery and Alzheimer's disease and some orphan disease. And we're also interested in applying our technology, this cyclodextrin technology and the cyclodextrin dimer technology, to other disease targets. Things like these retinoids that accumulate in the eye, causing macular degeneration, other oxysterols, and other targets as well.

And our technology is also applicable to things that aren't in aging. So, of course, it's technology, and so we think it could be valuable for overdose reversal, so for... you know, for anti-skin rash stuff, like things like poison ivy, things like that.

We're really hoping to be partnering with experts in other fields, and we're starting to have experts in those fields call us and say, can we use your technology for our problems? And we're really looking for partners and partnerships in those realms. And we're also looking for other ideas of things that we can target.

ideally things that are relatively small and hydrophobic. So things that are, say, a thousand or fewer Daltons in size and ideally hydrophobic that we can target with our technology. We have this powerful computational platform that we've built where we can take any target and throw it in and model cyclodections and make predictions about new ones that we can bind.

with them. So give us your ideas and we'll try them and we have a new AI training algorithm that we're training using thousands of simulations that we've already performed that we hope to be able to use so that it doesn't have to be humans anymore coming up with the ideas for the structures of the drugs. We just plug in the target and ask the algorithm to tell us what the best drug to make and then we can make a prototype and try it out.

Transcript for:Oxidized Cholesterol and Cardiovascular Innovation

Transcript for:
Oxidized Cholesterol and Cardiovascular Innovation