Presentation Videos from the 2024 Rejuvenation Startup Summit in Berlin

As it says on the first slide here, we have achieved significant reductions in the burden of atherosclerotic plaque in mice and we intend to continue the way we started. With respect to the current standard of care for atherosclerosis, the big problem here, the thing that I’m going to beat you over the head with for five minutes or so, is that present treatments cannot greatly, rapidly, or reliably reduce the existing burden of plaque. But we can, and that is our value proposition.

Atherosclerosis is probably going to kill you if nobody does something about it. The rupture of fatty plaque that grows in blood vessels kills 27% of us directly via heart attack or stroke – and that is in a world in which everybody who can use statins is using statins. Further, that doesn’t account for the people who are killed less directly by the reduced blood flow to the heart that leads to heart failure. In short, atherosclerosis is not a good thing and is the greatest single cause of of human mortality, greater even than than cancer. The more plaque you have, the bigger the problem: looking at this great data from a 2004 Dutch study, your mortality risk is five times greater if you have five or six plaques evident in imaging than somebody who doesn’t have those plaques. You will notice the mortality risk is a very large range, by the way, as the type of plaque matters greatly; how much fat is in it, how much cholesterol is stuck in that plaque, how likely is it to rupture. Either way if your cardiologist can see five plaques in your major arteries you are not in a good place. You want to do something about it, but today what can you do about it? Not an awful lot.

Let me call your attention to two meta-analysis studies as good examples – there are any number of others we could look at – in which researchers looked over several dozen studies and thousands of patients. If you look at the numbers on the right, the percent atheroma volume is the percentage of the volume of the artery that’s obstructed by the plaque. We are looking for percentage change in that in that number. You want it lower, but if after 18 months of statin therapy the outcome is a range of minus 5% to plus 3%, well, that is not a great form of treatment. The standard mean difference is even worse, as it is essentially zero! So if you take statins for 18 months then your existing plaque is still going to be there at the end of the day. But the plaque is the story! It is the most important part of this, because there are large studies that show that if you can produce a 1% reduction in your percent atheroma volume – just 1% – then the the reduction in cardiovascular event risk is much bigger, on the order of 20%. But that takes 18 months or thereabouts and only a subset of patients actually achieve that outcome no matter how low their blood cholesterol. There are people taking combinations of the modern PCSK9 inhibitors and statins and despite very low LDL cholesterol levels they have existing plaque and it’s going to stay there.

Why am I pointing out this 1% figure? That leads us to the next slide, to make the point that in mice we can reduce plaque cross-sectional area in the aortic root by 17% over only 6 weeks of treatment. We look at a cross-sectional area at random in the body of the aortic root plaque to get that 17% figure, and if one assumes it will hold all the way through the slices of the plaque, then this is a 17% volume reduction, not just cross-sectional area. This is a big deal! The importance here is that we can reliably achieve this in mice, and we hope to be able to do the same in humans. You might ask how we achieve this outcome in mice, and the short answer is that use a LNP–mRNA gene therapy to make cells clear out localize deposits of excess free cholesterol – and I’m sure you you understand all the words in isolation but the context would probably help a little more. Excess free cholesterol is a feature of aging, and unfortunately it is also a feature of obesity – which is one of the reasons why a lot of the consequences of obesity appear similar to those of aging. Cholesterol is transported around the the body, it isn’t really made or destroyed locally, and that complex transport system breaks down in ways that give rise to localized excesses of cholesterol. That localized excess overwhelms the cell’s ability to make free cholesterol safe by esterifying it or incorporating it into cell membranes or attaching it to transport particles, and that free cholesterol is toxic. It is toxic in the liver particularly because the liver is the center of cholesterol metabolism; your liver function is greatly diminished and harmed by this this excess free cholesterol.

Now unfortunately this free cholesterol is undruggable. There is no “break down the cholesterol” mechanism operating throughout the human body, or even in liver cells, that you can adjust with a small molecule. You can’t bind and sequester enough free cholesterol with something like a cyclodextrin to get rid of these excesses without killing the patient first – by removing too much cholesterol from cell membranes. In particular LDL cholesterol in the bloodstream, which is the target of lipid lowering therapies such as statins, has a tenuous relationship at best with a localized excess of cholesterol that might occur at some place in your body. You can lower LDL cholesterol in the bloodstream as much as you like and it won’t really do that much to a localized excess of cholesterol.

That said there are human proteins that can act in conjunction to degrade excess free cholesterol. These proteins are just not expressed together in near all cells in our body. We took the best of these proteins, turned them into an optimized fusion protein, encoded that fusion protein in messenger RNA, and put the messenger RNA into a lipid nanoparticle that is targeted to the liver. We introduce the therapy via intravenous injection, it travels to the liver, it expresses our fusion protein in liver cells, and that clears out the excess free cholesterol in the liver. The liver is thereby restored to homeostasis and the result is systemic benefits throughout the body via removal of this age-related and obesity-related contribution to disease and dysfunction. It is not just atherosclerosis that is affected, but many other conditions as well.

We are heading in the direction of our our first human trials and our focus is on the rare genetic disease of homozygous familial hypercholesterolemia – that I will refer to HoFH from now on for the obvious reason that it is hard to say repeatedly. HoFH patients have enormous blood cholesterol levels, and over a lifetime that means that they exhibit accelerated atherosclerosis. Absent any sort of intervention these people die in their 30s – they are not not in good shape. There are very few HoFH patients, and this rare disease status means that the barriers are lower for FDA approval, and potentially fast track approval. This slide shows our timeline to clinical trials; note that I’m including our non-human primate studies in because I’m going to make a point about those in a moment. By late 2025 we are going to have efficacy data in a high fat diet model in cynomolgus macaques, but that runs in parallel with getting ready for the first clinical trial for HoFH in early 2026. Of course questions of time are essentially questions of money – all of this depends on raising a series A round this year, enabling licensing, GMP manufacture with a CDMO, IND-enabling studies, and all the rest of it. Everything is lined up, it just needs the funding and off we go. This timeline is 18 months to the IND submission, and you might feel that this is a long time – but this is in fact very fast in the world of biotech, as I’m sure many of you are aware.

But coming back to the non-human primate studies, here is why I wanted to mention our work there. It is an interesting aside there’s a company called Verve Therapeutics, you might have heard of them because they recently ran into trouble with one of their clinical trials, but back in 2021 they were riding high because they had just gone public at a something approaching a $1 billion dollar valuation. At that time, the only data they had was in non-human primates. They had not conducted human trials at that point, and our therapy is objectively better than theirs – which is just a better a better statin, in brief. It lowers LDL cholesterol, and thus cannot possibly reverse plaque, just as is the case for all of the other LDL lowering technologies. As I said, we will be in this position about 15 months from now with a much better therapy, which is hopefully food for thought for those who might be thinking about investing in us.

I should say that while you know that atherosclerosis is why we are running this program, the starting point, it is not where we will will stop. This is a first-in-class therapy that’s going to spawn half an industry’s worth of further effort, research groups and companies tackling the many age-related conditions that are aggravated by free cholesterol pathology. This really should be a hallmark of aging, and I’m sure that as the hallmarks expand somebody will add it. We have demonstrated that we can reverse the liver fibrosis of metabolic dysfunction-associated steatohepatitis (MASH). We have also demonstrated over the course of that preclinical work that this form of therapy is likely relevant to type 2 diabetes as well, as we have demonstrated improved glucose tolerance and insulin levels following clearance of excess free cholesterol from the liver. Further, there are numerous neurodegenerative conditions in which the lipid metabolism of the brain is relevant. Patients and models exhibit cells with lipid droplets in the brain; there is clearly something going wrong in there, and we believe that excess cholesterol is probably relevant. Similarly I can point out a range of evidence in the cancer field, in immunology, in a number of other rare diseases, in which cholesterol metabolism runs off the rails in some part of the body, and where a therapy like ours could treat these conditions. This work will obviously be undertaken by an industry that will come after us, not by us – atherosclerosis is a very big problem in and of itself, but there is an even bigger pipeline here.

In the remaining 10 minutes I’m going to take you through a very brief tour of our results in atherosclerotic mice. This is the high level only, we have much more data, but the most important data is of course what happens to the plaque. We’ll start with a really great picture of serum samples from a time series study. These LDLR–knockout mice are the model for HoFH, the human patients also have loss of function in the LDLR gene, meaning the liver can’t take up cholesterol so the blood is filled with gunk: lots of cholesterol, lots of triglycerides. As the picture shows, when you pull serum from these mice it is actually opaque because it has so much so much stuff in there, unlike normal serum which is clear. In this time series study we injected the mice once with our therapy, and then sacrificed them at various time points afterwards. You can see that by 96 hours, a single injection of our of our therapy has essentially reversed the problem in the serum. The serum is back to being clear; we’ve removed the gunk, and that contributes to an impressive effect on the plaque.

Next up is the data showing 17% aortic root plaque reversal that I mentioned earlier. Just to fill in the details here, we took LDLR knockout mice and placed them on the a high fat diet for 16 weeks to make them severely atherosclerotic, and then gave them six weeks of weekly injections with our LNP-mRNA therapy. We used a very broad range of doses, from 0.25 mg/kg to 1.50 mg/kg. Those who know the mRNA space will know you you won’t go far wrong by picking something between 0.5 mg/kg and 1.0 mg/kg – many therapies seem to resolve to that dose in the end, and perhaps there is some universal reason for that. In any case, we picked a range of doses and they all worked to reduce plaque, and when averaging across the groups we see the 17% reduction in plaque cross-sectional area. By the way, there is nothing stopping us from extending these study timelines – waiting a few weeks and introducing another six weeks of therapy with these mice. We haven’t done that yet but in principle we should observe a greater regression of plaque.

Looking at further data, we took the mice and put them on a treadmill at study close, prior to sacrifice. Bear in mind that these are not mice that will win any prizes for exercise capacity because they are fat and sedentary, but all of the treated mice, at whatever dose, regained cardiovascular function to a very sizable degree versus the mice who were still impeded by the severe atherosclerosis that they were suffering. I want you to note that this is a very broad therapeutic window, with no side effects and yet benefits were observed at all doses tried.

Now we’ll move over to the APOE knockout mice which are another accepted model for atherosclerosis in the general population. We conducted a study in which we compared our therapy with a statin. It starts the same way as before, put the mice on a lengthy high fat diet and then provide them with six weeks of treatment. In this case it was a single LNP-mRNA dose at 1.0 mg/kg alongside a reasonable 5.0 mg/kg daily dose of atorvastatin, a dosing level that will not provoke liver problems in the mice but should still provide a visible effect size on lipid metabolism. As the data shows, our therapy is not only much better than statins, but also synergizes with statins. It is important to note that all other treatments are complementary to ours, be that the Cyclarity approach, or statins, or PCSK9 inhibitors – they can all be used in conjunction. It is an enormous industry, there is room for everybody. Again, this six week treatment could be repeated. In principle you can keep going. You could take a break and conduct the treatment again for 6 weeks, and we would expect larger results on plaque composition and size.

An important point is we’re not just removing lipids from the plaques and thereby stabilizing them, but we’re also increasing the collagen content of the plaques. The lipids are effectively being replaced by collagen, and thus the result is a more fibrotic plaque which is stable and safer. Further, we’re not replacing lipids with calcium – the plaque is not becoming calcified. I’m not going to present data on that topic, but I will say that in these models we do see a reversal of calcification in these plaques. You should probably take that with the grain of salt given that LDLR and APOE knockout models are not specifically models of calcification – if you put 100 of these mice on a lengthy high fat diet, you will maybe see 10 or 20 that have that exhibit a large degree of calcification in their plaques, not really enough to robustly draw conclusions.

I’ll finish up by mentioning our team I think most of you know Bill Cherman and I, the co-founders. We come from a mixed investment and patient advocacy background in the longevity community. Morad Topors is a tremendously talented researcher who is here today so you should take the chance to talk to him – he has a very good background in cardiometabolic disease and is probably the world’s leading expert at this point on clearing cholesterol for therapeutic effect. Bobby Khan, our CMO, is a very reputable, very well-known cardiovascular physician who has put drugs through the FDA and gives us good advice on our forthcoming forthcoming clinical program. Of course I really should mention that none of this would be possible without our very talented lab team, who in this picture are standing outside one of the two restaurants in Syracuse, New York that you have to go to if you go to Syracuse, New York. Now you know! If you’re there go to this restaurant. Collectively this is now the world brain trust on clearing cholesterol for therapeutic effect, as that this program is only being conducted by us – nobody else has this, nobody else owns this, nobody else is working on this. We are the first-in-class approach to reversing cardiovascular disease.