In this session, Reason, co-founder and CEO of Repair Biotechnologies, offered a sneak peek into their product and technology – a Cholesterol Degrading Platform – enabled by genetically modified macrophages able to consume and degrade cholesterol plaques in arteries. Apart from showing promising results in mice, he also explained the mechanism of action based on which this approach works and compared them to other solutions to atherosclerosis, the #1 killer in the world, that are on the market or are in the process of development. Lastly he also offered some details about the opportunity to invest in their company.

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Presentation: Reason

  • I’ll go over the basics of atherosclerosis and then show why what we’re doing is novel and a big departure from the past approaches and very likely to work and solve the problem.
  • Contrary to the picture, plaque doesn’t just narrow the arteries, it also weakens them. So the two possible results are that either the plaque breaks and flows somewhere and blocks something, or the artery just ruptures. Either of those are horrible things and the least you get is a severe embolism somewhere in your body, which kills – a lot of people, in fact it is the primary cause of death in our species and many other mammalian species.
  • Atherosclerosis are both the #1 and #2 causes of death based on the World Health Organization. Some people debate whether it is 27% or 40% depending on the groupings, but anyway it’s a huge problem, at least a quarter of people die because of this.
  • What is the cause of atherosclerosis? It’s not really cholesterol, it’s macrophages. Your macrophages cells in tissue are in part derived in part from the monocytes that float in your bloodstream looking for problems. And when they find the problem – that the wall of your blood vessel is unhappy for some reason, they dive in and try to fix things. And the thing that they try to fix is that you have a bunch of gunk sitting in your blood vessel wall that needs to be ingested and thrown back into the bloodstream, so it can go back to the liver. Unfortunately as you grow older, macrophages become increasingly incapable of dealing with this problem. And what you get is visualized on the right – macrophages to become foam cells, because they are completely overwhelmed by cholesterol, because they stopped being able to process it properly. From there it just gets worse and worse and more pathological, you get into the plaque situation. But the root issue is the macrophages – when you’re young, you are just fine, and blood vessels are not covered in plaque.
  • So why are macrophages not able to do their job later in life? We need to understand cholesterol transport first. Cholesterol isn’t created or destroyed in the cells, it’s rather ingested and excreted, but cells don’t break down or get rid of the cholesterol they don’t want locally, they hand it off to other cells and parts of the system when they no longer need it. Cholesterol is created in the liver, gets stuck on the LDL particles and goes into the bloodstream, gets stuck in a blood vessel wall, macrophages eat it and then throw it back into the bloodstream to attach to the HDL particles that flow back into the liver. LDL and HDL particles do pretty much the same when you’re young and old, it’s the macrophages that stop doing their job.
  • So why exactly do they stop doing their job? Due to a variety of issues listed in the slide – namely systemic inflammation, systemic oxidative stress, and too much cholesterol, although the last is probably not the worst of those three.
  • What all this leads to is a feedback loop. Your plaque is a macrophage graveyard, and the signaling of that draws in even more macrophages trying to fix the problem. That is the underlying problem that causes atherosclerosis.
  • As you are aware, there’s an entire research community and pharmaceutical industry focused on purely lowering LDL cholesterol – taking that part of cholesterol transport from the liver to the rest of your body and tuning it down. This probably helps a little, since you’re reducing oxidized LDL, you end up with less altered cholesterol in the plaques, so you’re giving macrophages a little bit more breathing room. But it doesn’t work enough, even if you reduce LDL to 10-20% of what is normal in humans, you won’t get rid of the plaques, you won’t reverse it.
  • Even after decades of focus on lowering LDL, atherosclerosis still kills that 27% of everyone. And the drugs that we use still achieve only 10-20% mortality reduction, while the number being heavily debated as it is likely too high, many trials have shown no improvement.
  • Furthermore, whatever you do with blood cholesterol, if you already have lipid-laden soft plaque, there just aren’t any good options – getting rid of it is not on the table.
  • So we need a better way forward – yet all the companies are still focusing on lowering LDL cholesterol – some of those latest therapies from companies going public are trying to charge $500,000 per year for that.
  • What are the alternatives? Let’s start with those that don’t work. I mentioned that systemic inflammation is one of the problems leading to atherosclerosis. But if you reduce inflammation systemically, studies suggest you get about the same benefit as you would get from lowering LDL cholesterol. Which doesn’t mean that somebody cannot come up with a way that could do this in a better and more targeted way, but the tools available for systemic inflammation are really blunt right now.
  • The second alternative sounds much better, if your ceiling is mice. Reverse cholesterol transport is the pathway when macrophage sucks up cholesterol and hands it off back to the bloodstream. There are a number of genes involved in this – macrophages use ABCA1 to hand off cholesterol to the HDL particle initially and then ABCG1 helps add more cholesterol to the particle. Then the particle heads to the liver and is excreted and ejected from the body. Anything you do in mice to make one or more parts of this system work better, it all works great – up to 50% reversal of plaque lipid content in some cases. But every time it was tried in humans, it failed – there’s a whole list of clinical trials over the last 20 years that tried and failed. That tells us that we don’t understand something very important about the way in which cholesterol transport is rate-limited in its different steps in humans vs in mice.
  • So our approach is to make macrophages resilient to the environment in old tissues.
  • There have been a number of people trying this, some of it hasn’t made it very far, some of it is interesting, and sometimes there is overlap between those two. There is a recent paper with a hypothesis of effect they showed is that if you target lysosomes in macrophages with antioxidants, it prevents the oxidized LDL particles from messing things up, and therefore more macrophages are doing their job – reversing the plaque by 50% in a mouse model. It’s entirely possible their hypothesis is wrong and delivering antioxidants is improving something else in the picture, but it’s certainly something self-experimenters should pay attention to because these antioxidants are easily available.
  • Secondly there is the Underdog Pharmaceuticals approach – sequestration of 7-ketocholesterol, which is a highly toxic altered cholesterol, thought to play a big role in atherosclerosis. Unfortunately, the only way to really see whether it works is to test it in humans, because mice just don’t have enough 7-ketocholesterol to make a difference here. So we’ll see how they do, I hope it works.
  • Lastly there is our approach – genetically engineering macrophages to give the ability to degrade excess cholesterol, whether or not it is altered. The company is named Repair, since I believe that if you’re going to address aging and you can’t point to something you are actually repairing – a form of damage or dysfunction, where you can clearly say that you are fixing this – then you might not be doing the right thing.
  • We’re currently working with an investment bank on a capital raise for our clinical round, so that requires me to show this slide.
  • In summary, what we’re doing is taking a stepwise approach of allowing macrophages to degrade cholesterol and stepwise approaching the various atherosclerotic conditions in order of number of patients. So starting with an orphan condition – homozygous familial hypercholesterolemia, then you go into larger patient groups as you gain experience doing this. Unlike most therapies, we can actually apply ourselves to any form of atherosclerosis, whether or not it is genetic, we don’t care how you got plaques, we just break them down.
  • We’ve demonstrated our AAV delivery of our cholesterol degrading protein – has a very large effect of 40% in a month, which is very big in the scheme of things and compared to other approaches. Our goal is to produce a universal macrophage cell therapy
  • As I said, atherosclerosis is basically the encounter of an aged macrophage with cholesterol at which you get a lot of cells eath and cholesterol-based plaque. If you overwhelm existing systems of normal macrophages with excess cholesterol, they can’t do anything with it and basically become foam cells – they don’t have an inherent way to deal with that level of cholesterol.
  • So with that picture in mind, the whole spectrum of LDL lowering cholesterol drugs really only lowers the input to the problem. And they can’t lower it infinitely, because the macrophage is in the plaque, not in the bloodstream, and the plaque is packed full of cholesterol and toxic horrible nastiness, so you’re not really getting a lot of boost from lowering the input from bloodstream – the problem is the plaque that’s sitting there. You can’t reverse it by doing this LDL lowering approach, you still have macrophages exposed to excess cholesterol becoming horrible foam cells already.
  • And the horrible foam cells leading to your plaque gives you this point that has to be made to a lot of people unfortunately. Your risk of death is not due to LDL cholesterol, it’s due how much plaque you have. It’s exactly how much plaque you have and how much high risk plaque – the soft plaque. That determines your mortality. LDL cholesterol, while widely accepted as a surrogate marker, is just irrelevant, it’s not the cause of your death. That’s why different people can have different levels of cholesterol in their bloodstream and have quite divergent mortality rates.
  • And the fact that it is the plague is why we have this list of drugs, starting with the ultracheap statins and heading up to the ultra expensive ANGPTL3 inhibitors, which frankly are probably not much better than the PCSK9 inhibitors. Because lowering cholesterol can do at most 20% mortality reduction, no matter which way you do it and how much you pay.
  • The point of the exercise is to figure out what we should do differently – and that is making macrophages invulnerable to the plaque-based environment as best as we can. Our idea of best we can is to give a macrophage the capability to break down cholesterol safely locally. I should say that this is not a trivial thing to do, because a cell is basically an enormous lump of cholesterol – our body uses cholesterols everywhere in the cell membrane. The reason why we never evolved to break down cholesterol when it’s harming us is because our cells have cholesterol everywhere. So you couldn’t evolve something that just chews cholesterol whenever it sees it. And that’s why delivering things like cyclodextrins, as Underdog Pharmaceuticals is not quite simple either, because the first thing that will happen if you dump a bunch of cyclodextrins into somebody is that their blood turns to mush, because it will consume all your blood cells by hooking all the cholesterol out of cell walls. Underdog has a way around that, but they need to be very careful with that.
  • So the objective is a safe way of breaking down cholesterol, but only the excess cholesterol, which is what we achieve by putting in these specific mechanisms into these cells we’re working with.
  • We can demonstrate that by putting these mechanisms into any old cell, and the output is exactly the same – we get a catabolite that is safe and more soluble, and leaves the cell into the bloodstream where it gets rid off. It’s a technology that can be used pretty much anywhere.
  • What this means is that we can take macrophages and give them the ability to express our CDP+ proteins, and then if you dump cholesterol on them, the unmodified ones become very unhappy – the green is a foam cell behavior where they ingest cholesterol inside them and becoming pathogenic and inflamed. in the right image, showing the modified macrophages, you see very little of that behavior – they just eat the cholesterol and get rid of it. On the left you see incomptent macrophages in the plaque, on the right competent ones able to break it down – that’s what you want in your plaque.
  • Our proof of concept with AAV, we delivered a very high dose of AAV into atherosclerotic mice, and you can see the difference. Red in the cross-sections of the aortic route is lipid-laden plaque, and we’ve got something like 50% reduction in the plaque in a month following a single treatment – this is a very powerful effect.
  • So going forward, we take the iPSCs from mice or humans (from our partners offering well characterized human lines), the lines are then disrupted in certain ways to make them universal (you get rid of the surface markers that make them recognizable – very important technology that gets you off the shelf line of universal cells, you can look at Sana delivering universal iPSCs to primates and showing no meaningful immune reaction). We then differentiate macrophages that express CDP+ ourselves from these universal cells, and this is the way we produce a cost effective cell therapy. We’re already injecting mice with these cells over the last month and we should have some data within a year.
  • And then what we do with this is a stepwise approach through the orphan indication with very few patients and a much easier FDA process, then to the indication with more patients, and then to high risk subpopulations of atherosclerosis. People who have had scans with a lot of high-risk plaques. Ultimately we think you can take the lion’s share of death – 27% by atherosclerotic diseases – and use technology such as ours to completely remove that cause of death from humanity. How long is it going to take? Who knows, but the first most high-risk population is where we start.
  • So our pipeline looks much like this, as I just told you. The market sizes are increasingly enormous, with $22B for atherosclerosis subpopulations probably being an underestimate.