NewAmsterdam Pharma Company N.V.

Good morning, everybody. Thank you for joining us today for our annual investor day. I'm pleased to have Michael Davidson, our CEO, John Kastelein, our chief scientific officer, and BJ Jones, our chief commercial officer, here with us today speaking, along with many members of our team. Ian Somaiya will also be available for questions afterwards for the presentation. Before we get started, The fun part, we will be making forward-looking statements today. I would advise everyone to please read our forward-looking statement page either here in the room or also available online at this time. As we mentioned, today we'll have Michael going through a general corporate update and introduction. We'll have John presenting the science, then we'll go back to Michael for an update on Pervail, as well as some of the updates on AD, and then BJ will be going through commercial. At this time, I'd like to have Michael come up and join us. Michael.

Thank you, Matt, and thanks, everyone, for being here. We're very excited to share with you our science and corporate update. For us, this is our third Investor Day Science Day, and for John and I, it's one of our favorite days of the year. We get a chance to talk to you about what we're doing at New Amsterdam, all our... Achievements, of course, for us, the most exciting thing about the company is developing new science, helping patients, and so we really want to share with you all our insights and where we are, and look forward to your comments and questions afterwards. So we have a new mission statement that I'd like to review with you. Our mission is to hold a new standard of care for people living with cardiometabolic disease by challenging Connections with courage, transferring deep biologic insights into meaningful patient impact in delivering with rigor, precision, and purpose. This is how New Amsterdam Built to Go Beyond. And so we have thought about all this, each word and what it means for us. And of course, we always believe in our other motto, which is expect more. We believe Obacetrapib is the type of drug that you can expect more when it comes to delivering better patient outcomes and improvements across multiple disease modalities. I'd like to start, as all of you know, I still see patients four days a month at the University of Chicago. I run the Lipid Clinic. This is a patient of mine, Frank, who's been with me for almost 40 years. And I bring this up because when Frank came to see me for the first time at age 36, he had super high cholesterol, LDL, he had diabetes. Thank you very much. That drives me and I think in many ways helps me encourage all our great advancements we have in New Amsterdam and motivates us to make sure that we can deliver better medicines to make a difference in people's lives. So let's talk about the New Amsterdam Value Proposition. We have good clinical expertise. That's been our background. John and I have been in this field for 40 plus years. And I think, as you'll hope to see in our discussion today, We designed our clinical development program to maximize success, especially Prevail. A lot of learnings have gone into how we went about designing Prevail and the modifications we made in the Prevail trial. Most important of all is the success of Prevail and how that will build value for both in Amsterdam and for patients. Obacetrapiv, of course, We're blessed with a great drug. This drug not only lowers LDL, but has multiple effects on many different biomarkers of cardiovascular risk. And of course we're very excited about the new data on Alzheimer's prevention that we believe is going to be a hallmark of this drug going forward. Now the unmet need is is something that we focus on all the time. Like I said, I still see patients and if you read JAMA this week, they have a great article about the global impact of high LDL and six million lives lost, 90 million morbidity events every year due to high LDL. And if you look at the maps, you know, the U.S. population, the LDL levels have basically flatlined. They have not changed in almost more than 20 years. And the mortality rates haven't changed. If not, they're going up. And so, you know, we're all excited about all these new therapies, GLP-1s and so forth. But we all know that, based on the data, heart attack rates are same or climbing. Stent PCI rates are climbing. So heart disease continues to be The leading cause of death and LDL levels that are elevated is the main contributor to that. We have been really focusing on building out our team and I'm excited to have BJ share with you the great additions to the team that we've had in the last few months. Remarkable people, some of them here today. We appreciate if you have a chance to meet them and hear about their backgrounds because it is a phenomenal team that we're developing across the company. Now, KL support continues to build. We've had MSLs in the field for more than two years now, and the feedback we're getting from the KL community is really very encouraging and inspires us to keep going and to prove the benefits of Obaceptifib across the disease spectrum. And our CMC team, we don't talk about this too often, but it's a phenomenal team. They just won the Green Chemistry Challenge Award, which is kind of like the Nobel Prize of Manufacturing. And we're very proud of that team and all they've accomplished. But I think the most important thing for the value creation is to develop a very robust supply chain for Obocetrapib and the fixed-dose combination in preparing us for launch in Europe and across the world. And the final point, again, is where we are moving forward as a company, and we're really excited to share with you where we're going today and into the next few months. So the accomplishments, just to highlight for you the key things across all our data with Broadway and Brooklyn and Tandem, you know, building out our team, and doubling in size and now more than 100 people and opening up a new office outside of Philadelphia along with our office in Miami and Amsterdam and of course we've been blessed with securing a large amount of financing on our cash balance of 678 million which gives us plenty of cash to launch this drug when the time comes. So let me give you a few important kind of key takeaways from the market itself. Again, I have this insight in my own practice of what's going on. I think we can say that The market is growing. You heard today even from Amgen about the growth, 37% globally, 50% growth in Repatha in the last year. So this is an incredible growth in the lipid market. The guidelines have been revised recently to go back to goals, you know, 55 LDL for the very high-risk patients. That's a huge number of patients that are going to be added to the number of patients that need to be treated to get to the adequate levels to reduce cardiovascular risk. and the other important attributes are the FDA guidelines, sorry, the FDA labeling that they're allowing now for lipid drugs is getting broader and payers are responding to that and we've seen much more broader access for all the LDL lowering therapies. For us, This represents a market, and BJ will go into more of the detail later, this is a market that's growing, growing robustly, the guidelines changing, it still hasn't reached the impact it's going to have, new entries in the market's gonna grow the market even more, so we feel we're really in a great position with Obacetrapim to really do very well, and I'm very confident that the drug will launch exceptionally well across the world. And we're excited about our first regulatory recognition from the CHMP, have recommended for approval by the EMA. For John and I in particular, I'll just focus on John, we've been working on CTV inhibitors for for 25 years, and to have the first one approved by a major regulatory body we think is a huge milestone, and we're very proud of this accomplishment, working with our Menterini partners, and therefore we're all set to potentially get approval in Europe in the very near future. So a very exciting time for us with this regulatory recognition. So now for the science update, where we're going, and like I said, this is our favorite day of the year for us to get in front of all of you and talk about what New Amsterdam is developing around the lobocytopenia as well as what other things that we're considering when it comes to how to differentiate this therapy from all other LDL-lowering treatments. I'd now like to turn it over to John to go through that science. Thanks, everybody. I'll be back.

Like the Terminator. Can I go one back? Yes. So I've really done my best to add new science into my lecture because I do know we're not the only company that you have to listen to. And so the last thing I want is that everybody is bored to death and then leaves and then thinks, oh, well, the coffee was nice, but that was about it. So I've done my best. And I would like you to leave this room a little later With our teaching that CETP is so incredibly central to human biology that it does way more if you inhibit it than just simply lowering cholesterol. And I think that is by far the most important lesson and we have a number of presentations coming up at the ESC at the end of August at the American Heart. We have a paper, two or three papers about to come out with data that speaks to the additional effects of Obesetrapib. Not just simply lowering cholesterol, it's not a cholesterol lowering drug on its own and that's almost impossible because as you know, we've told many times before, Obesetrapib knocks this target out by 98.3%. So basically what you do is you create a rabbit. Thank you very much. And so inhibiting it is actually a very, very good idea. The only problem was is that in the last 25 years, as Michael was referring to, either the drugs were useless or the trials were useless. So we have finally arrived at a point where Michael and I and the entire team have designed the trials and we have a compound that can do what we've always wanted to do. And so this kind of rainbow you've seen before, but it kind of really highlights all the additional effects that no other lipid lowering drug has. You go from lowering lipoprotein little a, and I do understand we need Horizon to completely understand what that means. We'll get it at the American Heart Meeting. Then there's the whole particle stuff, but the biology, and I'll show you that, is so compatible with CETP driving small particles, and if you knock CETP out, there are no more particles to drive to. Then there's the LDL, non-HDL, small dense LDL cholesterol, oxidized LDL, so on the atherogenic lipoprotein part, we have influence on almost every biomarker that we can measure. But that's not everything and what's getting more and more important is the HDL part of things. So the HDL part of things without any doubt is driving what we see in Alzheimer, is driving what we see in renal disease, and is driving what we see in the diabetes part of things. And I'm going to show you today two analysis that it's very likely also contributing to the MACE outcomes. And in fact, the godfather of ApoB, Alan Snyderman, just two days ago published a paper from the UK Biobank, half a million people, that shows that HDL changes the relationship between ApoB and MACE. So the higher your HDL, The less ApoB can be bad for you, and that is a totally novel insight, and we have found exactly the same, and I'm going to present that at the European Society of Cardiology. So it's no longer only Lp particles, diabetes, but it's now also HDL that's becoming biologically important and of course also clinically important for us at New Amsterdam Pharma. The question, of course, always is when you start, actually it's interesting because it is a new target currently because there's no marketed CETP inhibitor out there. So what you would normally do if you develop a new PCSK9 inhibitor, for example, you go back into history and say, what did other PCSK9 show? And so I think that it's very, very learning to see what other CETP inhibitors actually showed in terms of changes in MACE. Now of course there are many, but there was only one reasonable one, which is Anacetrapib and Merck. And for that I would like you to go back and let these numbers sink in. So the last CETP inhibitor trial before us was Reveal. Reveal was Anacetrapib, a Merck drug, 100 milligram, inhibited CTP by 75 to 80%, not 98, 75 to N. It lowered LDL by 17%. But look at the number. This was the largest ever CVOT on the planet. 30,449 patients for four years. In fact, this year, Oxford is doing the 10-year follow-up of this trial. The seven and a half year follow-up showed that that 17% was actually, if you look at over the long run, conferring a much larger benefit than everybody thought. So this is a much weaker CETP inhibitor. and a third of that trial, a third of the 30,000 is 10,000 by definition, just as big as Prevail. So we have a trial here that's three times bigger than Prevail and so what we can do is we can actually look at that trial and say let's take the patients that are basically similar to Prevail, and what did a weaker CETP inhibitor with a lower LDL reduction did, because in this trial it did 9%. And that 9% is actually better than what was expected. If you calculate that 17% reduction and put it on the CETT meta-regression line, it should be 6. So that looks like a little difference, but in terms of percent, it is not a little difference. So actually already in reveal there was this kind of inkling that CTP inhibitors do better than just based on the CTP matter regression line. And so Oxford, we have a very good relation with Oxford and I think they are still the best trial people in the whole world. And this is a very interesting graph because this is tertiles. So every dot is 10,000 patients. And if you look at baseline LDL divided in tertiles, non-HDL, ApoB, and you look in the highest tertile, which has a significant overlap with Prevail, you see it's no longer a 9% reduction, but in fact for non-HDL it's 17, for LDL it's 13, and for ApoB it's 14. So it immediately tells you that if your baseline LDL is higher, Prevail is almost 100, the baseline in Revil was 60, so if you up the baseline, and then if you up the LDL lowering, we don't lower LDL by 17%, we lower it by much more than 17%, that you get much better MACE reduction. So for us, this is the best kind of example from the past of where our trial is going to. So in review, modest CETP and LDL reduction in 10,000 patients with a baseline non-HDL in the range of Prevail delivered a 17% reduction in MACE. So then the question becomes, if we've seen that with anacetrapib, what have we observed with OB and the FDC compared to anacetrapib? Because these data are recent, we can simply compare it. And in order to get an honest comparison, we did exactly what Merck and especially AstraZeneca did, is we ran an ideal analysis. And this is, we do pharmacokinetics in all of our trials. And people that have a level of Obesetrapib of less than 100 nanograms per ml, only 0.3% by the way, so a tiny group, they simply didn't take their drug. So we do an on-treatment analysis of Broadway, Brooklyn, and Tandem. And what kind of numbers are coming out of there? Well, this we will present at the European Society of Cardiology. In fact, LDL lowering in week four is 43.5. And at week 12, it's 41.1. So our LDL lowering, excluding patients that simply didn't take the drug at all from the beginning, is over 40%. But maybe even more intriguing, look at the HDL increase in those people. That is 140%. So this is Brooklyn and Broadway. What about our fixed-dose combination? And the numbers are truly completely PCSK9-like, 63% for four weeks, 61% for 12 weeks, and you see exactly the same kind of HDL increases. So this is the efficacy of our drug going into Prevail when you do an on-treatment analysis like AstraZeneca did for their PCSK9 in Jack and Merck did for their Phase 3 program with leaving out people that they didn't like on the basis of ultra-scentification, blah, blah, blah, etc., etc. So those are data of really patients taking our drug. So what we see when you look at these numbers is that Obie was observed to lower LDL more than twice as anacetrapib. And remember what I showed you. Baseline, about the same as Prevail, LDL lowering only 17%, and then the return was a 17% reduction in maize. Our drug is twice as good as that. I'm not saying we're getting twice the maize reduction, but it's definitely going to be better than 17%. So this is a trial evidence. This is an example of let's take a large trial that's very similar to our own trial. What did it achieve in the past? Is there any additional evidence for CTP as a good target for reduction? This paper is about to come out in circulation and I'm very proud of this. I'm only showing you one curve. So what we did here with a number of different groups from Swedish universities is we did whole genome sequencing in half a million people in the UK Biobank. So everybody in the UK Biobank has this entire genome sequenced and these are people that had a real mutation in CETP. So they lost one allele. It was a loss of function, completely no CTP. That means, by definition, if you have one allele gone, you still have one remaining. So your CTP is 50% less. So that would be similar to a CTP inhibitor, a very modest one, that inhibits CTP by 50%. We followed these people for a very long time. Look at the red hazard ratio for any atherosclerotic event. It's all a bit small, I realize that, but the hazard ratio is 0.65. And this is with a 95% confidence interval that is as tight as anything. I'm not allowed to use the Dutch kind of... Think for that. It's 0.65. So that is bizarre. How is it possible? How is it possible that a hazard ratio for events is so large in people that have only a 50% reduction in CETP? And the hypothesis for that is that besides lipoprotein little a and small LDL, would the HDL difference make a dent? Because think about this. In Reveal, the HDL difference was 100%. Our drug raises HDL cholesterol by 140%. Is it likely that that doesn't do anything at all? And for that we have to just take a look at the real genetics. Because if you look at real genetics, you have real people with real examples. So when did we discover that humans with lower CTP did actually better than the rest of us? And for that, This is a New York Times obituary. This is Louise Levi. She was part of the Jewish Ashkenazi Longevity Project. This was a project where the investigators looked for people that were able to play bridge when they were 110. or solve a puzzle or read the Financial Times and be able to report it again. So these were people that had all their intellectual faculties way beyond 100. Supercentenarians. Then they took DNA. And they looked at mutations that were more prevalent in those people than in you and me. And the first thing they immediately noted is that these people had 3.6 times more mutations in CETP. So they had lower CETP than you and me. This is an old study, but it was definitely the first that indicated That if you want to get old, you'd better have a low CETP activity. That was the first. The second very interesting observation was Japanese physicians. Where do we find people that have no CETP at all? Because Louise Levi had about a 30% less CETP. Are there any people that have no CETP? Yeah, and they're all in the Far East. I've tried my entire career in Amsterdam to find a family. And I found one. And it was a Japanese family that moved to Amsterdam for financial reasons. They worked in the financial district. I've never found a Dutch woman or a Dutch man with a mutation in CTP. And what's so highly intriguing and totally irrelevant for this discussion is that it's in areas where there's endemic schistosomiasis. So, low CETP protects against a parasite, immediately telling you that CETP is much more than just lowering cholesterol. It is a central biological molecule that has much more. Now, of course, Being protected against parasites is not that interesting for our discussion today, but do they have other properties? And this is extremely interesting, so you have to really remember this slide. So exceptional longevity. They actually get older than the rest of Japan. They have low risk for ASCVD. They also have low risk for Alzheimer disease. That was one of the first observations that made us, after Louise Levi, think about Alzheimer. They also have lower risk of AMD. Andy Hsieh, one of our workers in the department of BJ, in fact, went to Japan, talked to the Japanese investigators. We recalled these people. pushed them through an ophthalmology research, looked in their eyes, we have never ever found someone with AMD. And then the last thing, just about to be published, there's a lower risk of sepsis mortality if you have no or low CTP. So the biology is, I mean, all of it is good. You don't want CTP. CTP is something that you actually don't need. But then let me just dwell for one second on the actual lipid profile. Look in the left-hand corner. They have a 100% increase in HDL, 40% decrease in LDL and FOB, 40% decrease in Lp and no small LDL particles. It's like a frigging mirror of what our drug does. And that is so interesting so you actually can watch in the biology of human beings and people that have no CTP naturally and see that a drug that lowers CTP by 98.3% recreates the exact profile. Now, I've talked enough about LDL-ApoB and Lp . There's no use in talking about Lp as long as Horizon is not reported out. No small particles. I'll stop shortly at that. But the 100% increase in HDL, what is the consequence of such elevated HDL levels? Now, first of all, this is part of another presentation that I'll be holding at the ESC about the UK Biobank. There's a lot of epidemiology out there that tries to kind of make very high HDL look bad. I can tell you with great certainty that that's all BS. It is total, it is science that is so flawed and so biased. In fact, all high HDL in humans is caused by alcohol. And so first of all, it's very rare. Only 0.5% of men had it and about 2% of women had it. And so this analysis, not published yet, to be presented at the ESC, shows you actually in orange is alcohol amount consumed per day. And then you see above that HDL, so HDL from 90 to 100, from 100 to 110, from 110 to 140, above 140. These are people not on a drug. These are people in the general population with HDLs above 100. And you can see in dark blue that this is all explained by alcohol. So if you read another Eric Topol warning on X that high HDL is not good for you, remember my lecture and ask him whether this was adequately controlled for alcohol use, because it never is. It actually never, ever is. So the mortality associated with high HDL by observational studies is explained by alcohol-induced multisystem disease. Not only that, the reverse is actually true. So this is, if you look at the Alan Snyderman population on high HDL and ApoB, you almost see the same graph because we use the same database. He went to the half million people in the UK Biobank, we went there, and this is the relation between maize and HDL. You can see that it starts at 30 to 35. That's not good, you know, it's the first. But then if you go down, you can see there is no flattening of the curve at all. In fact, the higher you are with HDL, in fact, the better it is. So HDL levels are associated with less risk for MACE and less risk for all-cause mortality. And that is very hopeful for our drug. Because if it's true in epidemiology, I know you have to prove it with trials, but it becomes a very attractive hypothesis that if your HDL goes up, that the relation between ApoB and MACE changes and actually shrinks, and that would of course have consequences for the hazard ratio. Last thing, people saying, I mean, there are all these golden oldies that say, yeah, but you know, CTP inhibition, high HDL, it's not safe, it's not safe. Well, I don't know how much more evidence you need. This is revealed, 30,000 patients followed up for four years, seven and a half years, and now 10 years, This is the line of unity in the middle. This is every imaginable side effect that you can come up with. And there's nothing that is either on the up or on the down. So HDL was increased by 100%. And there's no single fatal or non-fatal event that actually was increased in these patients. 30,000 patients. So I think the debate on whether high HDL, when you increase it to a high level, is safe, is with these data, as far as I'm concerned, totally over. So when we take all that biology, Michael and I and the team decided to go with the evidence. Our trial program coming next is going with all of that evidence. And these are the names. And I have to say that They're all Dutch, but I didn't invent any of them. So I actually didn't come up with these names at all. Michael came up with Spinoza, and I think Rubens and Rembrandt came from other people in the team, definitely not from me. So these are two Dutch painters and a Dutch philosopher, Jewish-Dutch philosopher on the end. It's always to tease the Americans a bit. But these are the names, and I'll tell you what this is. I'll start with Rembrandt. I think everybody knows Rembrandt. What we wanted to show Because we have an outcome trial for Obesetrapib monotherapy. But what did we have in outcomes for the fixed dose combination? We didn't have anything. So we wanted something, and that is Rembrandt. We wanted to show that the fixed dose combination also had an outcome. And here the outcome is plaque. And you know, I mean, this is booming, booming business. Plaque burden, non-calcified plaque burden. So tandem, 50% LDL lowering, just so the Frixos combination lowers LDL at least by 50%. So Prevail is for the ultimate question about risk and benefit, but for Plaques, we didn't have Plaques in Prevail, so we needed Plaques, and for Plaques we did Rembrandt. So we didn't start right away, so we first went to a humanized mouse model. and actually checked whether our drug in a humanized mouse model lowered LDL and non-HDL. And it did. And then we went and looked into plaques. You can all do that in mouse models. But we were only interested in severe plaques, type 4 and type 5 on the bottom. And the data are stunning and they're published. So, in fact, the combination of Obicetrapib and Azidamide Lowered lesion area around the aortic root by 98%. That's kind of knocking it out of the park. And then on lesion severity, in brown is the fixos combination, green is azithromyc and blue is OB alone. But look at brown because that's the combo we're using in Rembrandt. 97% less of the most severe lesion. and this is exactly the lesion you want to you want to fight because the earlier lesions they don't give events it's the it's the advanced lesions that give the events so we had the biology we had the pre-clinical work and so then we decided let's go for a trial in humans we already know that our that our fixos combination did great in terms of goal attainment This is new data. What do we do if we use the on-treatment analysis? Look at less than 55. 82.6% goal attainment for the FIXOS combination. That is just as good as better as anything that is currently on the market for LDL lowering. So this is a number that is outstanding. And with that number, we now hope to show in this trial where we randomize 300 patients to the fixed dose combination or placebo for 18 months and actually in 18 months, which will be I think in 27, end of 27, we'll have the data. So why is Rembrandt so important for us? Look on the right hand side of the slide. There is a lot of increased utilization of this methodology, CT angio, for the diagnosis of cardiovascular disease. There's a lot of positive traction with this with cardiologists, and we have designed it to demonstrate the clinical benefit of the fixed dose combination. And last, important for you guys, this may support labeling as well as promotion. You can see it moving in that direction. And why do I say that? Because the technology just last week got FDA approval. So we are working with this technology and this company, Caristo, in Rembrandt. And then suddenly, we actually didn't know it, they, the FDA, said, this is approved. Your new CCTA imaging technology is approved. So this is... The technology we're using in Rembrandt. And so we are really, really looking forward. If you look at the preclinical data, and you look at the LDL data, and if you look at the numbers of patients that we get to goal, this is one of our crown jewels, Rembrandt. And here we are, fully enrolled. Our operational team is the best of the best. They've always Deliver trials earlier than promised with more patients than anticipated. So we have 323 patients enrolled in 50 sites across seven countries. An estimated trial completion is in 2027. So everything going to plan. Then, of course, we need a small discussion. We've discussed now the plaques, the non-lipid plaques, Rembrandt and everything there. There is still this small LDL particle and diabetes issue. Now, we've shown you in a previous publication, and so this is all published, is that if you pool Broadway and Brooklyn, that there is a 23% reduction in the new onset of diabetes. And we are not the only CTP inhibitor. In fact, all CTP inhibitors showed a reduction in type 2 diabetes. And why is that so important? Because you will in the future almost always Add a CTP inhibitor to a statin. And what do statins do? They increase the risk of diabetes. And that's why Obesetrapib is an ideal companion to a statin. Because the increased risk of diabetes by the statin is mitigated by the CTP inhibitor. And it's not a little bit, because 23% is actually one in four. That is a very, very significant number. And for that we designed the Rubens trial. And why did we design the Rubens trial? Because patients with metabolic syndrome, obesity, type 2 diabetes, insulin resistance, basically all the same syndrome, They have a lot of small particles. They have statins on board. They have elevated LDL, and they have diabetes by definition. Otherwise, they wouldn't own the trial. All of those components are being addressed by OB. So we call that the sweet spot. So these patients are truly the sweet spot. They are very often the patients that are not at goal. Their type 2 diabetes is not resolved. It's not solved or addressed adequately by the current drugs. And they have lots of small particles. They get heart attacks much earlier than people with just elevated LDL cholesterol because they have end abnormal LDLs, small particles, insulin resistance, toxic central obesity, etc., etc., etc. So, these patients are ideally suited for a trial with our drug. And so, that is what we planned. The question is, how might Obesetrapib reduce diabetes risk? The answer is very simple, through HDL. It's very simple. The higher your HDL, the lower your diabetes risk. So if you double HDL cholesterol, and I can go into the biology but I won't, you can take it from me that if you increase ApoA1 and small HDLs, you actually basically efflux cholesterol out of the pancreas and you make these cells survive longer. So you address that. You improve that. And then the science behind the small particles. It's also very simple. In diabetes, you have very high CETP. And if you have very high CETP, you have more small particles. In fact, remember those Japanese? They had no CETP and no small particles. So if you knock out CETP, you knock out the possibility to generate small LDL particles. What do statins do? Statins are fantastic drugs, but look at the right-hand bar, minus 57.5. Those are large particles. So highly interesting. Statins lower, preferentially, large particles. They're great LDL-lowering drugs, but all of the cholesterol they get rid of is in large particles. So what remains in a statin-treated patient are the small particles. So another motivation to use Obesetrapib in these diabetic patients, you are not only addressing their diabetes risk, But you're also addressing the small particles. And all of those questions we would love to answer in Rubens. This is a pooled analysis of the small particles in our phase three program. Look at the light blue bar. If you're diabetic, our drugs lower small particles by more than 90%. So an incredibly powerful effect on small... So the biggest portion of the cholesterol that is lowered by Obesetrapib sits in small particles. And so Rubens is designed to test all of these effects of Obicetrapib and the FDC. So here is the design. A hundred patients will go into Obi, a hundred patients will go into the Fixos combination, and a hundred patients will go into the placebo arm. So again, concentrate on the right-hand side. We have a large underserved population. Type 2 diabetes metabolic syndrome patients. These patients, of course, there's a lot of traction with endocrinology and diabetes, in contrast to Rembrandt, where there's traction with cardiology. We have Rubens designed to evaluate changes in LDL, small dense LDL particles, LP little a, and the last thing, again, not the least important. It may support LDL lowering in a type 2 diabetes syndrome population in the label. So both trials, Rembrandt and Rubens, are designed with the hope that we can get some of these data in our label in the United States. Now, I will end, and I hope I didn't kind of bore you to death. I'll move now from the heart to the brain. All our focus is on Prevail. So don't worry, don't worry that Michael and I are going like two scientists with a black hat on an attic and we're going in a direction where nobody wants us to go. Everything is on Prevail, but I think that a lot of our hearts Actually, although it's in the brain, our hearts is actually in this. So what is this link between cholesterol, CTP, and Alzheimer's disease? There's very, very old data to suggest that if cholesterol in your brain goes up, the chances of Alzheimer's also go up. And this is not when you're 80. This is when you're 40. So more and more scientists are beginning to understand that when you're an E4 carrier, that something is going wrong in your brain already in your 40s. And it's extremely mild in the beginning, but there is accumulation of cholesterol in certain cell types. And that cholesterol, when it sits there long enough, becomes oxidized like anything in nature. That leads to inflammation, and that starts a cascade that ends with Alzheimer's disease. It takes 30 years. And I can tell you one thing, it's easier to intervene when you're 40 than when you're 80, and everything is basically finished up there. So this is one very important thing. I'm sure you'll see more and more reports where there is cholesterol dysmetabolism in the brain as the ultimate basis for Alzheimer. The second is that ApoE4, the most important risk factor for Alzheimer's disease, and some of you who cover neurology will undoubtedly know that, is also a risk factor for heart disease. The neurologists don't know this, but E4 is coming out of our field. It was a lipid scientist who discovered E4 a long time ago. and he published a lot about it. He was actually from Los Angeles. There's a whole institute named after him there. And he understood that E4 is a risk factor and later on it became clear that it was also a risk factor for Alzheimer. So what is the evidence? that low CTP and E4 are intermingled in Alzheimer's. In fact, there is very good evidence. There's very good evidence that if you have low CTP that your Alzheimer-free survival is better, right-hand panel. And on the left hand side, other forms of dementia that are also ApoE4 driven are seen in lower frequency when you have lower CETP. So there is very good evidence coming out of genetics and Mendelian randomization data that low CETP protects the brain, especially if you're an E4. So Michael will tell you that it makes a hell of a lot of sense to get these E4 carriers before they have Alzheimer and then start these trials. Now, unpublished data, but what biomarkers are best? And of course, pTau217. We now have a link between pTau217 and amyloid and tauPET, and between amyloid, tauPET, and cognitive decline. I think the FDA is very close to allowing pTau217 as the biomarker for Alzheimer's disease. I don't know, maybe even next year. But what did we discover in Broadway? And this is being presented and published pretty soon. In these patients that were all heart attack patients, a lot of them actually had elevated PTAL. So something that nobody realized was that in our outcome trials, Approximately 40 to 50% of people are on their way to neurodegeneration. So there's a lot of hidden Alzheimer in people that are 70 and have had a heart attack. And it's not that strange because a lot of the risk factors are similar, but that it would be so incredibly high, 45.9%, with abnormal P-tau levels, that's truly amazing. We are writing this down and it's presented and I mean everybody is fascinated and you'll see many cardiological cohorts repeating this analysis that we did for the first time in Broadway. And then of course in Broadway, did we do anything on these APOE biomarkers? Last slide. In ApoE4 homozygotes, on the right-hand side, PTAU217 increased over one year by 12.67% and decreased by minus 7.8% in the OB arm. That is a 20% difference, highly statistically significant. So, low CTP protects against Alzheimer. In people with heart attacks, p tau 217 is very high, abnormally high. If you give OB, these levels go down. So that shouts or cries for a prospective trial to solidify that and then understand whether it's worth going into the next phase. And I hope that you'll leave with that notion that this intriguing drug that started a long time ago as something that raises HDL, in fact moved back to lowering LDL, ApoB, non-HDL, small particles, oxidized LDL, small dense LDL, and then was found out to also increase ApoA1, ApoE, HDL, lower Lp little a, and the whole works, and this is kind of the last A bit of the almost story fairy tale of what started as something very simple in fact is something not highly complicated but I would say highly fascinating. And with that I would like to give the floor to Michael who is going to tell what you really want to know. And that's about Prevail, of course, and also about where we are planning to go with Alzheimer and how we kind of handle that. Thank you very much.