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. We'll go back to Michael for an update on PREVAIL, 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 to 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 and Science Day, and for John and me, 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 and helping patients. We really want to share with you all our insights and where we are and look forward to your comments and questions afterwards. 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, and delivering with rigor, precision, and purpose. This is how New Amsterdam built to go beyond. We have thought about all this, each word, and what it means for us. Of course, we always believe in our other motto, which is expect more. We believe obicetrapib is the type of drug that you can expect more of 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. 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, very bad family history. I just saw him in the clinic a week ago, and he looks great. 76. He's lost a lot of weight. His diabetes is pretty much gone. He's got a very low LDL and no evidence of clinical cardiovascular disease. This to me is the inspiration 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 years. 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 New Amsterdam and for patients. Obicetrapib, 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. 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 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. If you look at the maps, the U.S. population and the LDL levels have basically flatlined. They have not changed in more than 20 years. The mortality rates haven't changed. If not, they're going up. 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 the same or climbing. Stent PCI rates are climbing. So heart disease continues to be the leading cause of death, and elevated LDL levels are the main contributor to that. I'm excited to have BJ share with you the great additions to the team that we've had in the last few months of remarkable people, some of them here today. We would appreciate it if you had a chance to meet them and hear about their backgrounds, because it is a phenomenal team that we're developing across the company. Now, KOL 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 KOL community is really very encouraging and inspires us to keep going and to prove the benefits of obicetrapib across the disease spectrum. 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 like the Nobel Prize of manufacturing. We're very proud of that team and all they've accomplished. I think the most important thing for the value creation is they develop a very robust supply chain for obicetrapib and the fixed-dose combination in preparing us for launch in Europe and across the world. 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. The accomplishments, just to highlight for you the key things across all our data with BROADWAY, BROOKLYN, and TANDEM, building out our team and doubling in size. We're now more than 100 people and opening up a new office in Philadelphia, along with our office in Miami and Amsterdam. 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. Let me give you a few important kinds of key takeaways from the market itself. Again, I have this insight in my own practice of what's going on, and I think we can say that the market is growing. You heard today, even from Amgen, about the growth: 37% globally and 50% growth in Repatha in the last year. This is incredible growth in the lipid market. The guidelines have been revised recently to go back to goals of 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. 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. We've seen much broader access for all the LDL-lowering therapies. Though for us, this represents a market, and BJ will go into more detail later. This is a market that's growing robustly. The guidelines are changing. It still hasn't reached the impact it's going to have. New entries in the market are going to grow the market even more. We feel we're really in a great position with obicetrapib to really do very well, and I'm very confident that the drug will launch exceptionally well across the world. We're excited about our first regulatory recognition from the CHMP, have recommended for approval by the EMA. For John and I, in particular, just focus on John. We've been working on CETP inhibitors 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 Menarini partners. Therefore, we're all set to potentially get approved in Europe in the very near future. A very exciting time for us with this regulatory recognition. 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 NewAmsterdam is developing around the obicetrapib, 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. Now I'd like to turn it over to John to go through that science. Thanks, everybody. I'll be back. Here's John. Like the Terminator. Can I go one back? Yes. 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. 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. 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. 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 obicetrapib, 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, obicetrapib knocks this target out by 98.3%. Basically, what you do is you create a rabbit from a human, if you kind of think about it. Because, in fact, most rodents don't have CETP. We have CETP, and it's a gene that we shouldn't have had. It's an evolutionary mistake for us. We don't need CETP at all, and inhibiting it is actually a very good idea. The only problem was that in the last 25 years, as Michael was referring to, either the drugs were useless or the trials were useless. 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. 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 Lp(a); I do understand we need HORIZON to completely understand what that means. We'll get it at the American Heart meeting. There's the whole particle stuff. 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. There's the LDL, non-HDL, small dense LDL cholesterol, oxidized LDL. On the atherogenic lipoprotein part, we have influence on almost every biomarker that we can measure. That's not everything, and what's getting more and more important is the HDL part of things. The HDL part of things, without any doubt, is driving what we see in Alzheimer's, is driving what we see in renal disease, and is driving what we see in the diabetes part of things. I'm going to show you today two analyses that are very likely also contributing to the MACE outcomes. In fact, the godfather of ApoB, Allan Sniderman, just two days ago published a paper from the UK Biobank, 500,000 people, that shows that HDL changes the relationship between ApoB and MACE. The higher your HDL, the less ApoB can be bad for you. 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. It's no longer only Lp(a), particles, diabetes, but it's now also HDL that's becoming biologically important and, of course, also clinically important for us at NewAmsterdam 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. What you would normally do if you developed a new PCSK9 inhibitor, for example, is go back into history and say, What did other PCSK9 show? I think that it's 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. For that, I would like you to go back and let these numbers sink in. The last CETP inhibitor trial before us was REVEAL. REVEAL was anacetrapib, a Merck drug, 100 milligram, inhibited CETP by 75%-80%, not 98%. It lowered LDL by 17%. 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. 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. We have a trial here that's three times bigger than PREVAIL, and 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? 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 CTT meta-regression line, it should be six. That looks like a little difference, but in terms of percent, it is not a little difference. Actually already in REVEAL, there was this kind of inkling that CETP inhibitors do better than just based on the CTT meta-regression line. Oxford, we have a very good relationship with Oxford, and I think they are still the best trial people in the whole world. This is a very interesting graph because this is a tertile. Every dot is 10,000 patients. If you look at baseline LDL divided into tertiles, non-HDL, and ApoB, and you look in the highest tertile, which has a significant overlap with PREVAIL, you see it's no longer a 9% reduction. In fact, for non-HDL, it's 17%, for LDL, it's 13%, and for ApoB, it's 14%. It immediately tells you that if your baseline LDL is higher, PREVAIL is almost 100. The baseline in REVEAL was 60. If you go up the baseline and then go up the LDL lowering, we don't lower LDL by 17%; we lower it by much more than 17%, and you get much better MACE reduction. For us, this is the best kind of example from the past of where our trial is going to. In REVEAL, 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. The question becomes, if we've seen that with anacetrapib, what have we observed with Obi and the FDC compared to anacetrapib? These data are recent; we can simply compare them. In order to get an honest comparison, we did exactly what Merck and especially AstraZeneca did: we ran an ideal analysis. This is, we do pharmacokinetics in all of our trials, and people that have a level of obicetrapib of less than 100 nanogram per mL, only 0.3% by the way, so a tiny group, they simply didn't take their drug. We do an on-treatment analysis of BROADWAY, BROOKLYN, and TANDEM, and what kind of numbers are coming out of there? This we will present at the European Society of Cardiology. In fact, LDL lowering at week four is 43.5%, and at week 12, it's 41.1%. Our LDL lowering, excluding patients that simply didn't take the drug at all from the beginning, is over 40%. Maybe even more intriguing, look at the HDL increase in those people. That is 140%. This is BROOKLYN and BROADWAY. What about our fixed-dose combination? 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. 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 III program with leaving out people that they didn't like on the basis of ultra-centrifugation, et cetera. Those are data of really patients taking our drug. What we see when you look at these numbers is that Obi was observed to lower LDL more than twice as anacetrapib. Remember what I showed you. Baseline, about the same as PREVAIL. LDL lowering only 17%, and then the return was a 17% reduction in MACE. Our drug is twice as good as that. I'm not saying we're getting twice the MACE reduction, but it's definitely going to be better than 17%. This is a trial evidence. This is an example of, let's say, a large trial that is very similar to our own trial. What did it achieve in the past? Is there any additional evidence for CETP 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. 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 U.K. Biobank. Everybody in the U.K. Biobank has his 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 CETP. That means, by definition, if you have one allele gone, you still have one remaining; your CETP is 50% less. That would be similar to a CETP inhibitor, a very modest one, that inhibits CETP by 50%. We followed these people for a very long time. Look at the red, actually, hazard ratio for any atherosclerotic event. It's all a bit small; I realize that 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 thing for that. It's 0.65. That is bizarre. How is it possible that a hazard ratio for events is so large in people that have only a 50% reduction in CETP? The hypothesis for that is that besides lipoprotein(a) and small LDL, would the HDL difference make a dent? 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? 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. When did we discover that humans with lower CETP did actually better than the rest of us? For that, this is a New York Times obituary. This is Louise Levy. 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. These were people that had all their intellectual faculties way beyond 100, supercentenarians. They took DNA, and they looked at mutations that were more prevalent in those people than in you and me. The first thing they immediately noted is that these people had 3.6 times more mutations in CETP. They had lower CETP than you and me. This is an old study; 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? Louise Levy had about 30% less CETP. Are there any people that have no CETP? They're all in the Far East. I've tried my entire career in Amsterdam to find a family; I found one, 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 CETP. What's so highly intriguing and totally irrelevant for this discussion is that it's in areas where there's endemic schistosomiasis. 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. Being protected against parasites is not that interesting for our discussion today, but do they have other properties? This is extremely interesting; you have to really remember this slide. Exceptional longevity. They actually get older than the rest of Japan. They have low risk for ASCVD. They also have a low risk for Alzheimer's disease. That was one of the first observations that made us, after Louise Levy, think about Alzheimer's. They also have a lower risk of AMD. Andrew Hsieh, one of our workers in the department of BJ, in fact, went to Japan and talked to the Japanese investigators. We recalled these people, pushed them through ophthalmology research, and looked in their eyes. We have never, ever found someone with AMD. The last thing, just about to be published, is that there's a lower risk of sepsis mortality if you have no or low CETP. The biology is all of it is good. You don't want CETP. CETP is something that you actually don't need. Let me just dwell for one second on the actual lipid profile. Look in the left-hand corner. Left-hand corner here. They have 100% increase in HDL, 40% decrease in LDL and ApoB, 40% decrease in Lp(a), and no small LDL particles. It's like a freaking mirror of what our drug does, and that is so interesting. You actually can watch in the biology of human beings and people that have no CETP naturally and see that a drug that lowers CETP by 98.3% recreates the exact profile. I've talked enough about LDL, ApoB, and Lp(a). There's no use in talking about Lp(a) as long as HORIZON is not reported out. No small particles. I'll stop shortly at that. The 100% increase in HDL—what is the consequence of such elevated HDL levels? 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 make very high HDL look bad. I can tell you with great certainty that that's all BS. It is science that is so flawed and so biased. In fact, all high HDL in humans is caused by alcohol. First of all, it's very rare. Only 0.5% of men had it, and about 2% of women had it. This analysis, not published yet, to be presented at the ESC, shows you actually in orange is the alcohol amount consumed per day. Then you see above that HDL. HDL from 90 - 100, from 100 - 110, from 110 - 140, above 140. These are people not on a drug. These are people in the general population with HDLs above 100. You can see in dark blue that this is all explained by alcohol. 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. The mortality associated with high HDL by observational studies is explained by alcohol-induced multi-system disease. Not only that, the reverse is actually true. This is, if you look at the Allan Sniderman population on high HDL and ApoB, you almost see the same graph because we used the same database. He went to the 500,000 people in the UK Biobank, we went there, and this is the relation between MACE and HDL. You can see that it starts at 30-35. That is not good. It is the first. If you go down, you can see there is no flattening of the curve at all. In fact, the higher you are with HDL, the better it is. HDL levels are associated with less risk for MACE and less risk for all-cause mortality. That is very hopeful for our drug. If it is true in epidemiology, I know you have to prove it with trials, 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, there are all these golden oldies that say, Yeah, but CETP inhibition, high HDL, it is not safe. I do not know how much more evidence you need. This is REVEAL. 30,000 patients followed up for four years, 7.5 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 is nothing that is either on the up or on the down. HDL was increased by 100%, and there is no single fatal or non-fatal event that actually was increased in these patients, 30,000 patients. 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 am concerned, totally over. When we took 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. These are the names. I have to say that they are all Dutch, but I did not invent any of them. I actually did not 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. These are two Dutch painters and a Dutch philosopher, Jewish-Dutch philosopher on the end. It is always to tease the Americans a bit. These are the names, and I will tell you what this is. I will start with REMBRANDT. I think everybody knows REMBRANDT. What we wanted to show, because we have an outcome trial for obicetrapib monotherapy. What did we have in outcomes for the fixed-dose combination? We did not have anything. 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 this is booming business. Plaque burden, non-calcified plaque volume. TANDEM, 50% LDL lowering. The fixed-dose combination lowers LDL at least by 50%. PREVAIL is for the ultimate question about risk and benefit. For plaques, we did not have plaques in PREVAIL, so we needed plaques. For plaques, we did REMBRANDT. We didn't start right away. 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. Then we went and looked into plaques. You can all do that in mouse models. We were only interested in severe plaques, type four and type five, on the bottom. The data are stunning, and they're published. In fact, the combination of obicetrapib and ezetimibe lowered lesion area around the aortic root by 98%. That's kind of knocking it out of the park. On lesion severity, in brown is the fixed-dose combination, green is ezetimibe, and blue is Obi alone. Look at brown because that's the combo we're using in REMBRANDT, 97% less of the most severe lesion. This is exactly the lesion you want to fight because the earlier lesions, they don't give events. It's the advanced lesions that give the events. We had the biology, we had the preclinical work, and we decided, Let's go for a trial in humans. We already know that our fixed-dose 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 fixed-dose combination. That is just as good as, or better than, anything that is currently on the market for LDL lowering. This is a number that is outstanding. 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. In 18 months, which will be, I think, in end of 2027, we'll have the data. 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, CCTA, 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. Last, important for you guys, this may support labeling as well as promotion. You can see it moving in that direction. Why do I say that? Because the technology just last week got FDA approval. We are working with this technology and this company, Caristo, in REMBRANDT. Suddenly, we actually didn't know it; the FDA said, This is approved. Your new CCTA imaging technology is approved. This is the technology we're using in REMBRANDT; we are really looking forward. If you look at the preclinical data, you look at the LDL data, if you look at the numbers of patients that we get to goal, this is one of our crown jewels, REMBRANDT. Here we are, fully enrolled. Our operational team is the best of the best. They've always delivered trials earlier than promised with more patients than anticipated. We have 323 patients enrolled in 50 sites across seven countries. An estimated trial completion is in 2027. Everything is going to plan. 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. We've shown you in a previous publication; this is all published, is that if you pool BROADWAY and BROOKLYN, there is a 23% reduction in the new onset of diabetes? We are not the only CETP inhibitor. In fact, all CETP inhibitors showed a reduction in type 2 diabetes. Why is that so important? Because you will, in the future, almost always add a CETP inhibitor to a statin. What do statins do? They increase the risk of diabetes, and that is why obicetrapib is an ideal companion to a statin, because the increased risk of diabetes by the statin is mitigated by the CETP inhibitor. It is not a little bit because 23% is actually one in four. That is a very, very significant number. For that, we designed the RUBENS trial. Why did we design the RUBENS trial? Because patients with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance—basically all the same syndrome—have a lot of small particles. They have statins on board. They have elevated LDL, and they have diabetes by definition; otherwise, they couldn't have owned the trial. All of those components are being addressed by Obi. We call that the sweet spot. 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 is not solved or addressed adequately by the current drugs. They have lots of small particles. They get heart attacks much earlier than people with just elevated LDL cholesterol because they have abnormal LDL, small particles, insulin resistance, toxic central obesity, et cetera. These patients are ideally suited for a trial with our drug. That is what we planned. The question is, how might obicetrapib reduce diabetes risk? The answer is very simple. Through HDL. It is very simple. The higher your HDL, the lower your diabetes risk. If you double HDL cholesterol, I can go into the biology, but I won't, you can take it from me that if you increase ApoA-I and small HDLs, you actually basically efflux cholesterol out of the pancreas, and you make these cells survive longer. You address that. You improve that. The science behind the small particles is 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. 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, - 57. 5. Those are large particles. Highly interesting. Statins lower preferentially large particles. They are great LDL-lowering drugs, but all of the cholesterol they get rid of is in large particles. What remains in a statin-treated patient are the small particles. Another motivation to use obicetrapib in these diabetic patients, you are not only addressing their diabetes risk, but you are also addressing the small particles. All of those questions we would love to answer in RUBENS. This is a pooled analysis of the small particles in our phase III program. Look at the light blue bar. If you're diabetic, our drugs lower small particles by more than 90%. An incredibly powerful effect on small. The biggest portion of the cholesterol that is lowered by obicetrapib sits in small particles. RUBENS is designed to test all of these effects of obicetrapib and the FDC. Here is the design. 100 patients will go into Obi, 100 patients will go into the fixed-dose combination, and 100 patients will go into the placebo arm. Again, concentrate on the right-hand side. We have a large underserved population of type 2 diabetes and metabolic syndrome patients. These patients, of course, have 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(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. 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. I will end, and I hope I didn't bore you to death. I'll move now from the heart to the brain. All our focus is on PREVAIL, don't worry. Don't worry that Michael and I are going like two scientists with a black hat on in 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 are actually in this. What is this link between cholesterol, CETP, 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. This is not when you're 80; this is when you're 40. 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. Takes 30 years. That, 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. 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's. 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. He understood that E4 is a risk factor, and later on, it became clear that it was also a risk factor for Alzheimer's. What is the evidence that low CETP and E4 are intermingled in Alzheimer's? In fact, there is very good evidence. There's very good evidence that if you have low CETP, 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. 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. Michael will tell you that it makes a hell of a lot of sense to get these E4 carriers before they have Alzheimer's and then start these trials. Unpublished data, but what biomarkers are best? Of course, p-tau217. We now have a link between p-tau217 and amyloid and tau PET, and between amyloid tau PET and cognitive decline. I think the FDA is very close to allowing p-tau217 as the biomarker for Alzheimer's disease. I don't know, maybe even next year. What did we discover in BROADWAY? This is being presented and published pretty soon. In these patients that were all heart attack patients, a lot of them actually had elevated p-tau. Something that nobody realized was that in our outcome trials, approximately 40%-50% of people are on their way to neurodegeneration. There's a lot of hidden Alzheimer in people that are 70 and have had a heart attack. 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 everybody is fascinated, and you'll see many cardiological cohorts repeating this analysis that we did for the first time in BROADWAY. Of course, in BROADWAY, did we do anything on these ApoE biomarkers? Last slide. In ApoE4 homozygotes on the right-hand side, p-tau217 increased over one year by 12.67% and decreased by -7.8% in the Obi arm. That is a 20% difference. Highly statistically significant. Low CETP protects against Alzheimer. In people with heart attacks, p-tau217 is very high, abnormally high. If you give Obi, these levels go down. That shouts or cries for a prospective trial to solidify that and then understand whether it's worth going into the next phase. 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 ApoA-I, ApoE, HDL, lower Lp(a), and the whole works. This is kind of the last bit of the almost story, a fairy tale of what started as something very simple, in fact, is something not highly complicated, but I would say highly fascinating. I would like to give the floor to Michael, who's 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 handle that. Thank you very much. Thank you, John, as always, for the great science overview. I know this is, I'm sure, on all your minds, and of course, it's on our minds about how we can look at PREVAIL as we have our blinded data ongoing and improving our success with this trial. I think it's important to take a step back and talk about the history of NewAmsterdam and how the PREVAIL study was initially designed. I think all of you who've been following us for all these years know that we started PREVAIL at the same time as BROADWAY and BROOKLYN in tandem, three phase III trials along with the cardiovascular outcome trial, without having enough funding to complete the trials. We had to realize we had to raise money along the way. We designed PREVAIL. We think an excellent design. It was 10,000 patients. Again, a lot based on the REVEAL upper tertile, as John went through with you, understanding the relative risk reduction in that population, looking at the various four-point MACE endpoints. In thinking about the powering of that trial, we felt we were in a good spot to achieve a 20% relative risk reduction. Again, knowing the background about REVEAL and our more effective LDL-lowering treatment with obicetrapib, we thought was a really good design, 10,000 patients. We decided instead of having a much larger trial, like FOURIER, for example, which was close to 30,000 patients, like 27,000 patients, instead of having bigger study, we go longer to achieve a number of events. You can have more patients or go longer to achieve the same number of events. That was our initial design. The BROADWAY trial comes out, fortunately, confirming our hope for a relative risk reduction. It was 21% relative risk reduction in the four-point MACE that was the CTTC standard event rate, which we'll talk about in a minute. Then we were able to raise a significant amount of funding, and with that funding and looking at the BROADWAY data and the event rates that we had predicted, we wanted to move beyond the 20% relative risk reduction and look at a 15% relative risk reduction powering because now we had the resources to do that. That was a decision we made. We announced that I think last year at this meeting. The rationale really is the ultimate value for NewAmsterdam Pharma Company is based on a successful PREVAIL. We wanted to maximize success and further power the trial, which means we need to have more events to do that. Also, as you're aware, we did modify the four-point MACE to give us more power, and I'll go into that in just a few minutes as well. Keep in mind the background about what we've learned about the previous CVOTs. We know this, of course; we have many trials to look at. The higher the baseline LDL, the greater the benefit when it comes to absolute and relative risk reduction. In fact, there's this nice paper showing above 100 LDL relative risk reduction is greater than below 100 LDL risk reduction, even if you correct for the absolute LDL lowering. Having above 100 is a nice threshold to achieve a greater likelihood of success. We wanted to, again, go longer. We saw the mistakes that were made with FOURIER, for example, when you looked at the 2.2-year median follow-up. Just look at people that had at least one year of drugs; that would have gone to 20% if that was the decision that was made. It didn't take moving out longer to make a big difference in the relative risk reduction. The other, of course, point is the potentially enhanced commercial profile versus other lipid drugs. We believe that at the end of the day, a successful trial is the most important thing, whether it's 15% or 20%, but of course, 20% is better from a commercial perspective. We can utilize that. We wanted to, again, enhance that ability to get to the greater relative risk reduction. Those were all put into the design of the trial up front with PREVAIL. Here's now a figure to explain the changes that we made. We started off with a MACE 4 definition that was urgent revasc, cardiovascular death, non-fatal MI, and total stroke. There was a standard definition that was used by a lot of trials. Since then, there's been a movement from urgent revasc to total revasc for two reasons. One is that care has changed, that there's been really a pushback for patients just basically having no symptoms and getting a stent put in. That has changed dramatically with the COURAGE and the ISCHEMIA trials. Even the U.S., which had the highest kind of intervention rate, we're seeing much more of a change from elective revasc to not necessarily urgent, but revasc that's driven by symptoms and new onset of symptoms. The definition between urgent and total became much less of a distinction. Almost everyone now getting a revasc has symptoms that are increasing, and therefore, it's very close to the urgent revasc definition. When you look at—because urgent means within 24 hours. You have to have a symptom and get a procedure within 24 hours. Elective technically means they come in, they have chest pain, they get CAFD, and they get a stent that maybe takes two or three days. That would count as elective. The difference really aren't that much anymore clinically. The total revasc and the urgent revasc, and that's been adopted by FOURIER, by CLEAR Outcomes, by VESALIUS. All the recent trials have moved to a total revasc, which happens to be the same definition as the CTTC, the broad collaboration of all the cholesterol-lowering trials. It meets that definition. Just as an example, HORIZON is using urgent revasc still. It's not an entirely, completely total revasc, but it's moving in that direction. For MACE 3, which is still very important, I think this is a question we get quite a bit is why. It is a secondary. It's our first secondary endpoint. It's an important endpoint, of course, among the regulators, especially in Europe. They want to see the harder MACE endpoints. Even the FDA has made comments about that they want to see the overall benefit across all the four-point MACE and if the benefit's restricted almost entirely in the revasc, it's a review issue for them. It's not that you don't get approval, but it does increase your risk that you want to make sure that you do achieve MACE 3 benefits as well. That's a secondary endpoint; then we define this more precisely based on what LDL lowering achieves with treatment. We focused instead on cardiovascular death, coronary heart disease death, which is fatal heart attack and sudden death. Heart failure death, which we know is not affected by LDL lowering, is taken out of that definition. Stroke goes into the fatal, non-fatal stroke definition. We still capture that in the stroke endpoint. There is a slight difference between cardiovascular death and coronary death, but the precision about LDL lowering is more linked to coronary heart disease death. We move to that definition. Again, that's the CTTC MACE 3 and MACE 4 endpoint. Non-fatal MI is universal. That's actually the event that is most affected by LDL lowering. The most consistent reduction is if you see the trials, the non-fatal MI rates are what you see the most likely high relative risk reduction. Then fatal and non-fatal stroke, I'll get to in a minute, but that's ischemic stroke that we changed that from total stroke, so we don't have hemorrhagic stroke, which we know is, again, not affected by LDL lowering. This is, again, the learnings from these trials, the changes that have been made in other trials to focus on the LDL-driven endpoints, and that's why I decided to make that change for PREVAIL. It does add about 20% more events to move from urgent to total revasc. It does make that difference. That added more events into the PREVAIL trial to give us more power to achieve that 15% relative risk reduction. Here is the PREVAIL at initiation. We have not purposely published a design paper yet because we're following up the amendment through the FDA on these changes just recently. This is the initial design, the four-point MACE, including the urgent revasc and the other less specific three-point MACE considerations. We roughly had 1,000 events as our powering for that 20% relative risk reduction. Again, we had a minimum follow-up of two and a half years, which we think is one of the most important attributes of PREVAIL. We had a minimum follow-up of two and a half years. A lot of the trial shortfalls have been going too short, especially for the minimum follow-up. As we know, after the first year, you don't achieve the benefit that you achieve in years two and three and beyond. The point we want to make, and I think we made this when we announced the interim analysis, is that our interim analysis that we are achieving, stopping at the December timeframe, and then we're going to take time, of course, to adjudicate these events and analysis and so forth. We'll have the data available in the first quarter of 2027 to the DSMB to give us the decision whether we met our stopping rules. That is actually more events than we would have had originally to stop the trial. That's actually more events. We have said this publicly also that with a BROADWAY-like effect, we feel encouraged that the study will stop at that point, with our thresholds that we have not announced publicly, but we're keeping that private because that is important. We have, of course, applied in that stopping role all the important attributes of what a regulatory approval would be. The FDA is reviewing this and so forth. This would obviously mean a P less than 0.01 for the primary endpoint. The secondary endpoint also of three-point MACE also needs to be statistically significant. Those are the important points about the interim analysis. It is; we believe I'll talk about why we feel encouraged by that interim analysis stopping the trial. Most importantly for us is that we want to make sure that we maximize the chance at the end of the trial as well. That's where we go about to the end of 2027. We will achieve enough power to get to that 15% P value for the primary endpoint of four-point MACE. That'll be three and a half years of follow-up, of course, and a lot more events. That is the key decision we made, even though it would take that extra time. We think it's extremely important to make sure that even if the interim does not stop the trial, that we have a positive trial in the end. That is everything that we've done to maximize success. We're doing that with the PREVAIL trial. Again, the CETP world, as you know, has been one of not good fortune, and we want to make sure we maximize chance of success with the PREVAIL trial in the end. Again, I want to highlight for you why we are encouraged by the interim analysis, being that it is the time point where the trial will be stopped. The first is the BROADWAY data itself. What was exciting about the BROADWAY data is that in the first year, which again is more than expected, we saw this 21% relative risk reduction. I guess this is the same endpoint that we have in PREVAIL, the four-point MACE. Again, the CTTC definition. That was 0.79 hazard ratio. Again, the lines are superimposable at the first six months. At the second six months, we see this hazard ratio of 0.66. If we added our BROADWAY to BROOKLYN pooled data, we did get statistical significance in that second six months. We're very excited about that when we see the MACE benefit there happening earlier and greater than expected for the amount of LDL-C reduction. Getting to everything that John talked about with the attributes of obicetrapib. We ask questions. People have asked us, What about the breakdown of the different events? Yes, it was driven a lot by the coronary revasc, and that's what you'd expect. In a trial like this, the first thing you see go down is the revascularization rates. That's the most acutely affected thing by LDL lowering. We know that from other trials. We also saw a benefit on total mortality in the right direction. The four-point MACE I talked about. The coronary heart disease death was also in the right direction. Ischemic MI, of course, was also in the right direction. The stroke was the one that was really not that many strokes, but it was in the wrong direction that affected the overall MACE reduction. Those were small numbers in general. Again, the trend was in the right direction for most of the components of the four-point MACE, especially for total coronary revascularization. What about stroke? I know there were people that were pushing us to take stroke out because of this data. I think with small numbers like that, you don't want to be misled by that. We've looked again extensively at all the stroke data across all the trials. What you see consistently is that in the first year, there's really no effect of stroke in these trials. Over time, stroke becomes a contributor to the overall benefit. For us, we want the stroke benefit in our label. That's how it works. You have to have it in your primary endpoint to get it in your label. That, again, if we're talking about a dementia prevention discussion, you talk about LDL lowering for vascular dementia. We think obicetrapib for hopefully, with our science bearing out, it'll be obicetrapib for the Alzheimer's-related dementia. That's what we want to achieve with our continued data from all our trials. I can only say that as we track the stroke rates in PREVAIL, I believe we made the right decision. We're seeing low rates of stroke going forward and seeing those decline as much, if not more, than other events that we'll talk about in a minute. We feel we've made a really good decision on the stroke inclusion as one of the endpoints in the four-point MACE. The only stroke trial endpoint that's out is the HORIZON trial, which does not include stroke, which I think is maybe a mistake. That may be why their event rates are lower than expected also. They don't have that in their three-point MACE. The other point I want to make is that when you look at how the phase III lipid trials' MACE events correlate with CVOT data in the future. The concordance is very remarkable. If you saw phase III MACE benefit in these trials, you saw a benefit in the CVOT. At four out of four lipid trials, we saw the same relationship between the MACE reduction in phase III and the ultimate results in their outcome studies to follow. It's another important kind of correlation that we think is worth mentioning. We published this paper recently as well. Now let me talk about BROADWAY and PREVAIL. Again, this is the key reason why we're optimistic or encouraged by the interim. The BROADWAY study was started at the same time as PREVAIL in many of the same sites with the same DSMB, even more important, the same adjudication committee. These are all looking at events in the same way. As you can see, the risks of these patient populations are very similar. BROADWAY was ASCVD. It did have about 10% of patients with familial hypercholesterolemia without ASCVD, but 90% had ASCVD. PREVAIL is all ASCVD, and it has a little bit higher baseline LDL. Generally speaking, these are very similar populations. That means that the event rates in BROADWAY give us a really good signal about what the event rates should be in PREVAIL, especially at the placebo event rate of each study, can really give us guidance about how our event rates will track over time. As we shared with you in the past, what we see is, again, encouraging, that for the first six months, the event rates in PREVAIL track exactly what we saw in BROADWAY, and then as BROADWAY lines diverge, Kaplan-Meier curves diverge, we see the PREVAIL data basically staying in the middle of the two lines as event rates. You can see the blinded one-year event rates are almost identical overall. If you look at the components, which we haven't talked about, each of the components are almost identical. CHD, death, urgent revasc, you want to use it, stroke, non-fatal MI, all the events look very similar in PREVAIL first year versus BROADWAY first year, blended event rates between the two. Over time, we're seeing these event rates in PREVAIL go down even more, which again is our encouragement about why the interim study will stop the trial with DSMB review. Not only that, besides BROADWAY, which we think is the best kind of comparator on event rates, again, the HORIZON trial and the OCEANA trial don't have those comparisons to make. Remember, the baseline LDL in HORIZON is 60. I think OCEANA is probably similar. I don't know if they've actually disclosed that or not. 60 LDL versus 100 LDL that we have in PREVAIL gives you a framework of event rates. Again, they don't have a stroke in there. We have a stroke. Otherwise, the event rates are captured in a similar way. If you think about a 40 milligram per deciliter difference in LDL, what HORIZON doesn't know is what is the contribution of high Lp(a) in that population? Once you wipe out LDL and you wipe out Lp(a), how much events are being driven without those two being present? If very low LDL, you have very low Lp(a). That could explain why the event rates are lower than expected. Again, OCEANA has announced again with the Amgen earnings call that their event rates are lower than. They pushed the study out later. We feel that HORIZON, I know a lot about people ask us about HORIZON and what that means for us, and we can talk about more about that in the Q&A session. We believe, as John has talked about so much, that our drug goes well beyond Lp(a) lowering, which is one of the great benefits of the drug when it comes to cardiovascular risk reduction. We believe that HORIZON, whatever it shows, is going to be a positive for us because if it shows a trend in the right direction, that on-treatment would have been better because we know that it's been a challenging study for continued maintenance and so forth for multiple reasons. That if we see a positive benefit of Lp(a) lowering, but it doesn't meet approval or has issues like side effects and so forth, we believe the go-to Lp(a) lowering drug initially on the market. That's something that we're excited about, and that we think HORIZON, no matter what it shows, is going to be a very important readout for us, but not entirely. We have our own data, BROADWAY, showing 21%, and we see these, again, very encouraging event rates. With that said, not only do we look at BROADWAY, of course, but what we have the advantage of versus other trials is we have a lot of LDL-lowering trials to look at. We also have a lot of other CVOTs that have recently been done that can evaluate event rates, and FOURIER being the landmark trial that people go to. Everyone who designs a trial now looks at FOURIER as the event rates because that was a large trial. It's stable ASCVD, which is our population. And you can see the event rates there are roughly 5% and 3%, which is standard you do for these type two trials. Then we have SOUL, all diabetes, again, with higher event rates than SELECT, which was another GLP-1 trial without diabetes. You can see the diabetes makes a big difference in event rates. Now, both SOUL and SELECT have LDLs around 80, and SELECT has no diabetes, SOUL has diabetes, and so you can see the difference in event rates. SELECT becomes for us like the. We should definitely be higher than SELECT because, again, no diabetes and lower LDL—those are the event rates that we saw for three- and four-point MACE. Then CLEAR Outcomes is another good trial to look at. The most recent, higher LDL in the secondary prevention arm. But even in the on-treatment arm, when you look at the LDL levels that are more comparable to PREVAIL, we see event rates in PREVAIL ongoing that are much lower than these event rates in the blinded way. So we have a good opportunity to look across trials. It's always the challenge. There's a famous joke, really, is that a good way to lower your event rate is to be a placebo patient in the CVOT. We take that to heart. We really want to be careful about how we look at the data, but what we're seeing is very encouraging. That when we see the lower event rates in all of these trials in a blinded way, we can assume a certain placebo rate from BROADWAY, and that puts us in a setup for success with the interim, but more importantly, at the end of the trial, if we need to go longer to achieve the powering for completing the trial. Another question we get is, What about GLP-1 drop-ins? People are always questioning whether event rates are coming down because people are starting to use GLP-1s. I just want to highlight for you why event rates have dropped really is because LDL levels have come down quite a bit from the original trials. As LDL levels were treated effectively with statins, the newer trials had lower LDL baselines. We're driving LDL levels lower and lower. Those lower event rates are driven primarily by lower LDL levels in those trials. When you look across, if you adjust for that, the event rates have not really dropped at all in the more recent trials. They're pretty much flat. Again, that's the population. This data's really supporting that as well. LDL levels have stayed stable across the U.S. population, and heart disease rates are still as high as they've ever been. It's all an LDL-driven difference between these lower event rates compared to other trials in the past. That's why the HORIZON trial is probably lower than expected because that LDL level is so low. What would it mean for a drop in a GLP-1 into our trial? First of all, our drop-in rates are low. We are roughly a little bit over 1% per year in drop-ins of GLP-1s. We track that very carefully. The same for PCSK9; it's even lower than that. SGLT2 tracking: all these are in single -digits, low single -digits when it comes to drop-ins to these other therapies that could potentially affect MACE rates. If you looked at the magnitude of the benefit. By the way, we're mostly out of the U.S. In Europe and other countries, GLP-1 access is very limited. It's just the U.S. issue that because we're in the U.S., you hear more about the GLP-1 drop-in issue. If you think about it, for every 10,000 patients you treat, 100 patients are treated, and only one in 62 benefit from a GLP-1. For every 100 patients treated, you have a 1% drop-ins. For 100 patients, you get very few events actually prevented. We're talking about a low number out of 1,000 patients that actually would have a lower event rate due to GLP-1 drop-in. We told you our drop-in rates are very low. We do not believe this has any impact at all on our overall event rates. The overall event rates are the negligible effect on that event rate going forward. When we summarize where we believe PREVAIL is going, we also look very carefully at our drop-ins and drop-outs of other lipid drugs. PCSK9 is very low, statin stopping or discontinuing, very low, our off-drug levels are, compared to other trials, exceptionally good. Compared to CLEAR Outcomes or FOURIER or now with VESALIUS, we looked at all the most recent data. Our clinical ops team is exceptional; we feel really, really good about the execution of the trial, the quality of our trial, and so forth. We believe that cannot be an explanation for the lower event rates. We're doing everything we can to maximize finding all these event rates. What about the patient population changing? As we said, the LDL lowering across the spectrum. You've heard about other trials. Our LDL is 100. It's one of the highest LDLs of any trial. That does not explain a lower event rate in the placebo arm in particular. We believe this is not an issue about the patient population. Should be a high risk. It was designed that way. Higher LDLs and high diabetes rates—that's what PREVAIL is. The GLP-1 drop-in is, again, negligible and should have no impact on the overall event rates. We believe, and this is our reason why we're encouraged, that it's a treatment effect. We're seeing a great treatment effect of obicetrapib in line with what we saw on BROADWAY. I just want to point out that this is our view. We want to make sure at the end of the day that we don't jeopardize the overall success of the trial. We will go to that full powering for that P less than 0.01 at the end if necessary. Also, we've been asked about the alpha changes. It's really not an issue at all. It's not an issue for us on the statistical alpha spend. Does not affect our overall success of a P less than 0.01 in any way, shape, or form. I think to summarize all that, I hope you kind of understand where we were when we started and why we now have come to where we are on the PREVAIL powering and design to maximize success. These are obviously difficult trials to do, and we're executing extremely well. The most important thing, of course, is overall success. Again, we keep emphasizing that the BROADWAY benefit is what we see in BROADWAY. If we carry that over to the interim, we'll be in good shape. Again, our predicted placebo rates across multiple trials and, of course, in BROADWAY give us optimism that that'll be the case. With that said, I think we'll open up for questions later from the audience. I'd like to now just talk about SPINOZA for a second because I'm very excited about this, of course. John mentioned the name. I'll get to that in a second. This is a really exciting trial for the APOE4 patient community. We've been interacting a lot with the APOE4 Alliance, a patient advocacy group. Wendy, being one of the founders of this group, is an APOE4 homozygote. Her father has Alzheimer's disease, dementia, and she, of course, is E4 homozygote, is very excited to be starting in the SPINOZA trial as soon as it gets enrolled. This is an example of the unmet medical need here that we really want to emphasize with obicetrapib. As far as the pipeline is concerned for Alzheimer's drugs, we're unique. As John said, we're talking about lipid metabolism in the brain. The brain is totally separate from the periphery when it comes to the blood-brain barrier, separating the two. The HDL is what crosses the blood-brain barrier. There's no LDL in the brain. There's only APOE and HDL. We're very excited about this modality and obicetrapib being where it is. We can see that we feel we're in a really good place on the overall landscape of drugs that are being developed for the prevention or treatment of Alzheimer's disease. Prevention is what we're focusing on. What's exciting about the field right now is about the biomarkers and how we now recognize that 20 years before cognitive decline begins, there's evidence of the biological process already beginning. We see p-tau217 and other biomarkers increasing; they have very high predictive rates of going on to develop cognitive impairment. Now, somewhere between, based on our analysis, you have a 15%-25% conversion rate by having certain biomarker evidence of Alzheimer's disease converting from normal cognition to dementia, mild cognitive impairment, within five years. It's a very viable population to study to prevent cognitive impairment from happening in the first place. Again, APOE4 being one of the most important genetic factors, that's 25% of the population. This is, we believe, a very key differentiator for obicetrapib. As John showed you, the p-tau217 benefit is quite remarkable, especially in the APOE4 homozygotes. This p-tau217 data keeps getting better and better. Every week, a new paper comes out highlighting how exciting this biomarker is for predicting and using it as an endpoint for trials. We're very excited about where we're going to go with the SPINOZA trial. SPINOZA, where the name came from. John said, a famous Jewish Dutch philosopher. I'm Jewish, and John is Dutch, so it makes sense that we have a Jewish Dutch philosopher as the name of our trial. He was also a revolutionary in his thinking. He believed that religion should be rational, and although he didn't achieve acclaim in his lifetime, he is considered one of the most important fathers of the Enlightenment and in how we evolved into thinking about things in a more rational way. The most famous line about SPINOZA, I believe, is when someone asked Einstein, Do you believe in God? Einstein said, I believe in the God of SPINOZA. I think it's a very appropriate trial that we believe we're going to revolutionize how people think about Alzheimer's and the prevention of that with this study, and more to come in the near future about the initiation of this trial. That said, I'd like to now bring up BJ Jones, our Chief Commercial Officer, to highlight the exciting times we also have on our upcoming launch of obicetrapib. Thanks, BJ. Thank you, Michael. Hello, everyone. Very tough to follow these two gentlemen. It always is, but hopefully you can see how excited we are as an organization. I am personally, in regards to all the tremendous work that's been led by the balance of the rest of the organization, what Michael has led, what John has led, what our clinical operations team has done to get us to this point. Ultimately, our belief is that we're moving quickly now with a clear regulatory path towards what would be a commercial launch. I'm excited to bring you up to speed on the great work that we are actually doing. Hopefully you can hear me now. With that, what we'll do is we'll spend some time on the U.S. I'd also like to just bring you up to speed on the work that we're doing around the European launch, just partnering with Menarini and the support that we're providing to them for what is their imminent launch. As it relates to U.S. launch preparations, really we're focused on what are three pillars, and that's preparing the market, preparing the product, and preparing the company. Let's spend a little time on the market and what's happening and how that's evolving in the space. Michael mentioned it up front, and just started in the space of CV death continues to grow. Even with all the options that are currently in the market, we see that as an epidemic, and we absolutely, positively need to do something about it. We continue to do primary research, and we do that with patients; we do that with clinicians as well. Some of our recent data that's come back points to what is, again, what we recognize and know, but this is a tremendous unmet need that's out in the marketplace. This slide specifically speaks to patients and basically how they're reduced or difficult, dissatisfied in some sense with the treatment options that they currently have. Why? it's varied reasons why that type of thing. Basically, two out of three patients are saying that they are not satisfied with their hypercholesterolemia treatment. Really, the reasons why kind of fall into two general buckets, one of which is perceived or real lack of efficacy. The difficulty is patients basically communicate that they're taking their medications, they're still not reaching goal, have difficulty around that, whether it's just medication or even with the addition of what would be diet and exercise. They're just not achieving goal. The other bucket, in some sense, is safety and tolerability. Generally, again, with the use of statins, there's just kind of a consistent communication around how there are issues with muscle and body aches and things of that nature. All those things contribute to what is the dissatisfaction generally. What does that mean? Certainly, our industry recognizes what this is—a tremendous unmet need—and we see what is this driving innovation. There are, as you can see here, there are seven organizations, I'm not telling you anything you don't know, but seven different organizations outside of NewAmsterdam who are focused in this space, specifically around what is LDLC, and that's PCSK9 activity. Lp(a), of course. We have a lot of activity in that space, and in combination as well. What you see outlined below is just kind of a pipeline that shows the momentum. This is all public information, but essentially it's for those that are currently in the market, Lib, and of course, Merck more recently. You see where the other organizations are in terms of their relative pipelines and the progress they're making as it relates to their phase II data and then ultimately their anticipated approval. The investment in the space by this industry, again, it helps to reinforce what our broad conviction is that just this lipid management space is very big and tremendous unmet need, and that there's a focus to basically bring what is broader options to the marketplace to address the need for patients. How does that translate into general market dynamics? I continue every time I kind of show up with you all, I go through this and kind of give you an update on what's happening, and we just continue to see what is this dramatic growth in the market overall. As you can see here on the left-hand side, we see general patient population, now we've seen that kind of move out of the 70 million into the 84 million or so folks who actually are diagnosed with hyperlipidemia. Unfortunately, over 20 million of those folks actually are not on any, whether statin or any LLT. Over 40 million of those folks, unfortunately, are on a statin but just are not at goal. What that represents again is like 60 million patients out there who actually have a need, undertreated or not treated at all. Very robust, good for us in some sense, horrible, frankly, for patients. If you look as well at the progression from left to right, we just see the relative growth of the market. We see consistent growth of the overall market, which represents over 2% growth, and the vast majority of that obviously is driven by statins. As we move to the right, we see the non-statin market primarily driven by ezetimibe, but again, at almost 20% growth year-on-year, that's been consistent. As we go in the further right, we look at branded again now north of 30% on a consistent basis and obviously primarily driven by success of REPATHA. We just saw their recent data that popped out in terms of how they're doing. We expect, of course, to grow with the introduction of Merck's oral as well. What that leads to then is that tremendous growth in some sense, and what are some of the catalysts? Well, one of them, and we heard Michael speak about this earlier, is the recent update to guidelines. The interesting thing here, and it's actually a very good thing, is because those guidelines do advocate for what is more aggressive intervention. The FACILITATE data was phenomenal and basically says two major things, which are that you need to actually start treating earlier and with greater intensity. Those things we believe will actually impact the market in a significant way. In some sense, it's represented right in this slide, which on the left-hand side, we look at the number of patients and how the patients grow over time, and this represents those patients over the last few years, the addition to the market as a whole. The right-hand side basically suggests that the patients that are currently being treated are actually treated more aggressively over time as well. That is either increasing in terms of dosing the statins or, and we hope more and more, is add-on treatments to actually get patients to where they need to be. That's essentially kind of what's fueling what is this general growth. That leads to overall branded growth. We go to REPATHA just because it's the lead product in the space, it kind of tells the story, right? The story is that if you pass what's on the left-hand side, we obviously all know the story about how slow REPATHA was in terms of kind of getting up that learning curve. In recent years, we see nothing but accelerated growth in that space, incremental investment, and recognizing if they engage appropriately with clinicians and with patients, is that they're starting to really penetrate this marketplace. They're looking at last year at over $3 billion in terms of revenue, and the class holistically clearly will bypass what is $5 billion this year. I think it just helps us to recognize it's a massive market, but we're barely actually penetrating that space from a branded standpoint. It's much bigger, much more opportunity. We've got to reach patients to actually have an impact. Let's take a look now at the product, again, I go back to the great dialogue that we just had with John on sharing the science behind it and what Michael Davidson has suggested as well. That points to, again, what is so unique about Obi and Obi Z, and that is we're grounded in what is a comprehensive program. All the phase IIs, all the phase IIIs thus far have been successful. I want to just reemphasize our confidence in PREVAIL and just, again, its outcomes-driven clinical program. As a reminder, we'll be the only product that's actually launched in this space that has outcomes available. A big differentiator for us. We believe that ObE delivers what LDL-only therapies were never designed to offer, and this is what John just walked through in some sense. We importantly can address what the current LLT paradigm is, and that is we've got to address LDL-C. That's a priority for clinicians. We certainly understand that. With our data, we know with confidence that we can do that with equivalent efficacy, if you will, to PCSK9s appropriately. We can certainly do that. We look to change that paradigm going forward, and we'll take care and address what are particles, but it's that residual lipid risk that we can uniquely do in the marketplace. When we can do that, John also talked obviously about the relative benefit associated with increasing HDL as well, that is a very differentiated approach. The importance that clinicians actually see in that regard as well—I'll share some data in that regard in just a moment, the ultimate question is, where do you all fall? In the paradigm, what does this look like? We believe that Obe absolutely can redefine what this post-statin therapy is for those 60 million or so patients that are actually out there, not a goal. We start, of course, at the very top of the funnel with 84 million folks, then with statin therapy, there are 63 million. Not enough; 63 million of those folks are actually on statins. Unfortunately, the majority of them are just not achieving their goals. That leaves us north of 40 million who are, again, on medication but actually not achieving goal. We add the incremental 20 million or so who are actually not on anything, right? Which gets us to that 60 million or so. That's where we come in, is that we want to encourage, right, statin use and get everybody that's possible on a statin. We're the next step, and that's an all-in-one step. We've got to address what the initial objective is, which is to reduce LDL-C reduction, we can certainly do that; we just walked through that data. Approximately 50% reduction or so, but it's the broader lipid impact that's the differentiator. That's exciting for clinicians as we start to educate and communicate what is this broader benefit is It's safe and well-tolerated, as we know, and it's oral once a day, simple dosing. That is, again, what is this differentiated benefit in the marketplace? We know it'll have a big impact. Going back to that primary research, we talked about patients earlier. On the other side of that, we talk about HCPs. What's their perception? Generally, we ask them, How likely are you to prescribe Obi and Obi-Easy looking at RTPB versus that which is in the marketplace? As you can see, two out of three HCPs are in the top three box, which basically say they have a high propensity to actually prescribe in that space. I think it's important to recognize the reasons why, which are kind of communicated through the quotes. One is on what is not just efficacy, but broad efficacy and the perception of none of them can do what this medication can do, which is target ApoB, non-HDL, and Lp(a) which has eluded us in all this time. Specifically, communication from cardiologists—that's something that all clinicians actually see relative value in. A PCP around safety and tolerability. We have something that's even more effective at getting you to goal with minimal side effects, and it's safe to take with your current medications. Lastly, of course, convenience, and it's kind of this holistic approach. I would just say it's a novel product, once-daily oral, easy to use, that targets those harder-to-fix types of cholesterol, Lp(a), ApoB, and boosts HDL, which leads to better CV outcomes. Again, lots of feedback. We certainly have many more quotes, but it kind of anchors in these three different areas. That shows the relative benefit and the receptivity we expect, frankly, in the market when we join. At this point, I'd like to kind of shift a little bit to what's the work that we're doing behind the scenes to help us as an organization kind of evolve from what has been purely development to what is pre-commercial and ultimately will be a commercial organization. I have to say, this is my favorite slide in the entire deck, and I'm going to take a moment to kind of introduce this team of mine, which I could not be more proud of. This is the team that frankly can and will get it done. I believe in this statement up front: does this launch success require a great asset? We certainly have a great asset. We spent two-plus hours talking about the great asset. Talent is what really makes it work, and one of the things that one of you said earlier is about, are you going to be able to execute, BJ? I said, Absolutely, we're going to be able to execute, and it's because of this tremendous team. I'd like to take a moment to actually introduce you to my leadership team, this launch team, some of whom are actually in the room as we speak. You'll have a chance to spend some time with them. We'll start with Steve Albers. Fantastic human being. Better human being than actually even expert in this space. Steve joined us at the very beginning of the year. He joined us from Novo, in which he spent almost two decades there, kind of going up that leadership team. was most recently responsible for the entire portfolio at Novo, from pricing, access, as well as public affairs. kind of handles that for us now and found this to be that attractive to actually come and join NewAmsterdam Pharma. Fantastic job that he's doing with us already, and it's clear he will position us well with that set of constituents. Next up is Mike Austwick, who couldn't join us today. He's actually over in the U.K., but he is responsible, so essentially ex-U.S. we partner together on how can we maximize the opportunity in the rest of the world and actually get Obi into the hands of patients who need it more broadly. Mike and I actually worked together at AZ a few years ago or so. Tremendous broad commercial background. Most recently, he was actually on the board of Verona Pharma. Again, has very explicit experience around how you do launches, right? turn out to be a fantastic option for them. Next up is Chris Deluzio. Chris and I literally have. I won't age myself, but we have been together for over two decades at different organizations. What I can say is you will not find a better leader in our industry. He will actually lead the sales organization as well as our enterprise operations organization. Most recently, we shared success at Biohaven. He's going to bring that expertise here. He'll bring his network and ability to recruit true talent to NewAmsterdam Pharma. Next up is Serina Fischer, the newest addition to my team. Serina's sitting in the back and very excited to actually have her here with us, and she's head of global marketing. Serina and I have spent time; we worked together back at Takeda. Brilliant mind, will make sure that from a brand strategy standpoint, like a global brand strategy standpoint, we're on point. That's the work, excuse me, that she's currently doing even for the few months that she's been here. You'll get a chance to meet Serina. Next up is Deb Horner. Deb is here as well. Deb and I have spent time together over many years in many different organizations, but most recently at Biohaven. What Deb's responsible for is operational or launch excellence, if you will. She and her team drive the PMO. She will make sure that not just the commercial team, but the enterprise, the whole organization, is lined up and ready for what will be an impending launch. As we're well on our way of kind of making sure that we build the capabilities necessary to do that and do it effectively. Andy Hsieh, who's the head of Med Affairs, actually preceded me here at New Amsterdam, but actually has over 2-decade relationship with Michael. Brilliant mind, has helped us build essentially what is this medical affairs capability. Has hired and built a tremendous team. One of those individuals, Nancy Orzechowski, sitting in the back there, who's responsible for medical strategy and kind of our evidence generation, all that activity. I'll show you some of the great work that Nancy and her team have done in just a moment. Last but not least, Sanjay Kaul couldn't make it today, but he's actually here, the head of insights and analytics. He and his team are responsible for all the great work that we've done on primary research. Importantly as well, it's the analytics piece. Building the capability of how do we track and basically get feedback so we can optimize launch along the way. What Sanjay and his team have also been able to do is work very closely with Menarini to help them upgrade their capabilities in that space so they can look for an optimal launch as well. Let me spend a few moments on activity that's happening today in market, and that's where our medical affairs education, and we're investing appropriately in that space. It's all around developing what is Obi's scientific platform and the consistency around that platform. How do we communicate and educate in an effective way? How do we engage with KOLs and the broader clinical community and also continue to build value evidence? We certainly do that primarily in these four areas, which is publications, value evidence itself, field medical, and congresses. I'll just spend a moment in each of those areas. On the publication side, again, I just have to continue to point back to Nancy, who's responsible for building what is this tremendous capability. We are data-rich as an organization with Michael and John at the head of it. What do you do with that data? You build it into what are very compelling papers and publications, and we have over 26 peer-reviewed publications. You see where BROOKLYN, BROADWAY, TANDEM, have landed in some of the best journals in the industry. You see basically the overall readership of this. Again, we're represented extremely well, kind of, in the marketplace. We'll continue to do that, we're very excited anticipating what are the data associated with PREVAIL in the very near term. On the value evidence side, it's very important for us to generate healthy economic data and information. We certainly do that on a consistent basis with our phase III data. We've built a value dossier, or we're building a value dossier. We continue to iterate around that with the new data; real-world evidence is extremely important. We make sure that we communicate that in all the right platforms; that's great work that's currently ongoing. On the field medical side, we don't have many folks out there, but they are doing lion's work. Deployed MSL team, we've gone out and gotten the best and brightest who have extensive experience kind of in the marketplace overall, and they target KOLs specifically in institutions, broad scientific leaders. We go directly to payers as well and engage them effectively, and we've done that over time. At congresses, we're well represented as well. We're making sure as well that we have a big footprint, and our shadow basically is much larger than what is NewAmsterdam team. Lastly, from a congress presence standpoint, we are really making sure we're where we have to be for all the appropriate congresses, both here in the U.S. as well as over in Europe, as you can see, the major conferences. What's really impressive, and hopefully you agree, is that when you look on the right-hand side, the relative number of presentations that have been communicated and built in that capability again, like this is the outcome in 2024, 17 presentations last year, 40 presentations, and this year alone, 39, and we're halfway through the year. We continue to build, again, and have a very large footprint in the community. With that, the next thing is branded launch, right? That's what we're working on feverishly underneath the water just to make sure that we're prepared as an organization. We are very customer-centric. We're going to make sure that we're focused on bringing what is this transformational product to market, as we've talked about. It's a tremendous responsibility for us to do that, and we're prepared to do that, and we need to make sure we do it with a seamless experience for all the stakeholders aligned here. Now, I'm not going to go into a lot of detail at this particular juncture as it relates to how we do that. What I can say with confidence is that we're looking to embed innovation throughout. We know that we can do things in a very effective manner, but do it efficiently. There'll be efficient spend of resources, and we believe we can do more with less as well in regards to headcount. We'll get all that done. We know we're in a very big marketplace. We know we'll be battling, competing with what are big players. We feel very confident we can do that and do that effectively in this space. As a reminder, the market is so big, it's not a we win, they lose type of scenario. It is very big, certainly big enough for several winners in this space, and ultimately, that's a winning solution for clinicians as well as patients. Let me spend just a moment on the European launch update. As we all know, we got positive CHMP opinion just recently, great news and a fantastic milestone, as Michael said up front. First time for this MOA to get approval by a government body. We're extremely ecstatic about that. If we take a look at some of the similar data, it's very interesting to see that in the EU, the market is actually large but growing even more rapidly than what's happened in the U.S. Unfortunately, it's because patients are just not being treated to the degree that they need to. You can see the overall market growing at +7%, non-statins at 25%, and branded at 50% or so. We expect that to continue to grow, and we want to be right in the middle and in the thick of that with Obi and Obi Z. In a similar way, we see early demand for Obi reflected in primary research as well in the EU, specifically in the EU5, and these data essentially are a response to your likelihood for prescribing Obi and Obi Z within the first six months. Looks very similar to the type of data that we have in the U.S. as well. Very receptive audience, and we look forward to seeing that play out in the near term. As we look at EU regulatory and launch timeline, of course, we talked about the recent opinion, anticipated EMA approval would come in early Q4, then anticipated launch in both U.K. and Germany by Menarini at the end of the year, late in Q4. I do want to mention very quickly is that Menarini, we absolutely believe they're well-positioned to launch Obi, and it's driven by what is this kind of historical CV heritage that they have, leading share of voice and significant local presence. Menarini, again, has a very broad portfolio, and specifically within CV. So they have established relationships, and there's a lot of trust with the call points in that space. Importantly, as you can see here, and this represents the EU5, but whether it be general practitioners, cardiologists, and internists, they have extreme leading share of voice in that space. They will be where the patients are, and that's a key to success in that space. We look forward in terms of that partnership, and we're working very closely to make sure that they're fully prepared for what will be launched later in the year. As I close on this point before I hand it back to Michael, just want to reinforce the fact that, look, if approved, Obi Z can, and we believe will redefine post-statin treatment by getting patients first to LDL-C goal, which is the primary. We know that, but we can do that consistently with the competitors out there while also mitigating what is this residual risk. There's significant unmet need we had talked about, very large market, still growing, about $60 million in the addressable market for Obi, as we defined. Potentially the first LLT to launch. We know we have three very successful phase III studies, but the first to launch with outcomes data in hand. Can't express how important that is for us from a differentiation standpoint. Very powerful efficacy, as we've talked about, with that differentiation on Lp particles and the rate of new-onset diabetes. All of that within what is a simple oral, once-day, low-dose solution that's reported to have safety tolerability profile comparable to placebo. The medical affairs team, again, it's not just capabilities, but we're actually in market today with success and spreading what is education to the broader audience. Again, as I mentioned to you, the best team in the business and anxious for you all to get to meet them in the near term. With that, Michael, I can hand it back to you. Thanks. Thank you all again for coming. I think we're going to wrap up here and open up for Q&A. It's important that I think we're setting out here all our multiple readouts coming up, and I want to highlight those for you, the milestones and catalysts that we're going to have over the next few months to years. I start off with this. We're data-driven. We want to make sure that PREVAIL's successful. As BJ has highlighted and John has talked about, we have a very differentiated drug from any other LDL therapy. The unmet need is big and getting bigger based on the new guidelines. I hope you got a flavor for what we're recruiting here at NewAmsterdam under the leadership of not just the commercial team, which as you can see, is exceptional, but across the company, we're building out very accomplished industry executives. The KOLs are really rallying behind this and very excited about the new therapy. We also, of course, have the balance sheet to get us through commercial launch. Here's our readout kind of milestones over the next 12 to 18 months. RUBENS will be this year. It's all nearly nearing completion. We'll lock the database, and we'll have data at the very end of this year. PREVAIL, we talked about the CVOT, the interim analysis, timing-wise, we believe will hit the numbers by the end of the year, and then the readout in the first quarter of next year on the interim analysis. REMBRANDT, again, a very exciting study looking at non-calcified plaque as an endpoint, which is, again, becoming more and more established in the cardiology community. That'll be read out sometime in 2027. Starting SPINOZA. We believe SPINOZA is going to go quickly. The feedback we're getting from the patient community is overwhelming. Patients with APOE4 are knocking on our doors all the time to be in part of that trial. Then that we believe will be an important part of our whole launch differentiation as well, having that benefit that we've already established with the BROADWAY data. Then, of course, the tailwinds that's been talked about so much this morning, the guideline changes, getting LDL goals now established. Lp(a), again, HORIZON is important, and we're going to have Lp(a) lowering benefits on our label in Europe, as well as phenomenal HDL data. These are key differentiators of obicetrapib, getting momentum as a target. We're all waiting for HORIZON. People are looking at us until that data comes out a little bit, waiting for that data as a clearing event for us. Like we said before, we think it's a win no matter what happens with HORIZON. Get it out of the way, other trials to follow because this study itself may not be the best study to evaluate Lp(a), but we believe there will be a benefit there that'll support Lp(a) lowering. We believe we'll also be one of the primary drugs to go to when our drug is available on the market. We also have just seen this tremendous growth in the market overall that's going to allow us to very effectively launch the drug. With that said, I just want to again thank everyone for coming. It's always great. This is, like I said, one of our favorite days to get out there and talk to you, our investor community, our stakeholders. We love to get your questions -and -answers, hopefully good answers for what you're going to try to say in your reports and so forth. Thank you again for coming. Matt, we're going to have it right now, the Q&A, or take a break or— The team can go up. Okay. Go ahead and have John and Ian and BJ come up. We're happy to take your questions. Thank you. Very good. Well, you get seated. Tyler Van Buren, TD Cowen. Thank you so much for the interesting presentations. A couple for you. What can you say about the decline in event rates that you're seeing in year two of PREVAIL on a blinded basis, of course, relative to what is historically observed with CVOT outcomes trials? It would be great to hear you elaborate on that and what gives you confidence. The second question is, can you help us better understand the powering of PREVAIL at the time of the interim analysis? Do you have to report a MACE benefit similar to what was observed in BROADWAY in order to hit both MACE-3 and MACE-4 at the interim? Or is there a cushion on the lower side in case it ends up being closer to PCSK9s at 15%, at least from a MACE-4 perspective? Right. Thanks, Tyler. I think I'll let John elaborate, too. What I tried to portray is that obviously we're blinded, and these are blended event rates. The first year looks very similar to BROADWAY. That's, again, BROADWAY was designed to de-risk PREVAIL. Also, one point I wanted to make is that people have followed this since then, but we were the first to really put all the ASCVD patients into one large trial just for this very reason, to maximize the events into one single trial. We also needed it for the regulatory approval in Europe. They wanted to see MACE rates that did not show harm, so kind of like the diabetes regulatory process. We achieved that, of course, now with the CHMP recommendation. No one's ever had the benefit of having a trial that was done that has basically the same population as your outcome study, starting at the same time, the same sites with the same DSMB, the same adjudicator. We never had that before. If anything gives you a guidance on placebo event rates, it's BROADWAY. What we are trying to say is that if we impute a BROADWAY placebo rate into the blinded PREVAIL data, we look really good. We won't tell you what the numbers are. We are seeing BROADWAY-like relative risk reductions with that imputed placebo rate for both three-point and four-point MACE. That's how we look at it. The question about the power, again, we're not giving away exactly the numbers, but we do have some wiggle room. We don't have to be 20%. We could be lower than that. We're not going to give you the exact range, but we don't have to be 20% to achieve the statistical significance for both the four-point MACE and the three-point MACE, the way we have it set up. I think we just want to keep emphasizing that it's really a free look for us. The look is the same time we would have stopped the trial anyway. We did this to ourselves. We wanted to maximize chance of success, so we could have stopped the trial as planned right now at the interim. We felt that it was more important at the end of the day that we completely take all the risk as we possibly can off the study to make sure we have a final result that's positive. That brings us even a lot more power at the end, for closer to what you see with the PCSK9 15% relative risk reduction. If you look at all the trials, REPATHA 15% and FOURIER 19%, and CLEAR Outcomes 13%. ezetimibe 9%. We want to make sure that at the very least we have to be powering for a 15%. We just can't call the trial, and we hit something that's 15%, and it's not statistically significant. That would be, I think, a major mistake. It's an extra, potentially a little bit longer; you're close to a year, but that risk—we think that delay is well worth it. With that said, though, like I said, we can't be more clear that we are seeing these event rates that are low for both three and four. Just keep that in mind. It's both three and four that we're seeing these lower event rates. That if you impute a placebo rate from BROADWAY, we are in a good place for the interim to hit both the three- and the four-point stopping rules. Does that help you? Okay. All right. Yes. This whole discussion is muddied by the fact that Novartis, of course, and some KOL say, Yeah, all these event rates are decaying in all these trials. What they forget to mention is that if you control for LDL, event rates are not decaying at all. Therefore, the choice for a 60-milligram baseline LDL in HORIZON was a wrong choice. They are never going to say that about their own trial. Second, it might be that if you really knock down Lp, that the impact of Lp might be a little less. They're not going to say that either, because they're losing the market right there and then. The discussion is muddied by that a bit. Then people say, Well, all trials, events are going down, so PREVAIL will be automatically part of that. Scientifically, that's real hogwash. It's simply not true. Event rates have been extremely stable if you control for baseline LDL in these trials. By far the best determinant of event rates in your trial is your baseline LDL. I don't understand how you can, after having witnessed REVEAL was a failure, the one I showed, because baseline LDL was 60. If baseline LDL would have been 90, they would have a 26% reduction of that CETP inhibitor. What's happening now with HORIZON, they designed a trial where the baseline LDL is 60. We have a proverb for that in Dutch that I won't repeat here. Yeah. Good morning, team. Thank you for always an excellent presentation of science, commercial outlook, and really connecting the dots and learning a lot. Three really simple questions for you. One is, what is the probability that the interim concludes that you don't need to go till year-end next year in your view, based on the analysis that you have done? Question two is, why not not do the interim and just keep going till end of next year and report out, you have more events occurring and a greater probability probably to see a greater separation. The third one is for Ian, how do you envision the disclosure going to look like at the time of the interim? What can you tell us at that time point? I'm not going to answer any of those. All right, next question. Just kidding. That's from Michael. I will say the question, why not just do the study at the end? It's a good question. I think that we debated this, of course, a lot. The interim, though, was two reasons. One is the data that we were seeing. We're seeing the blinded data, and we're getting very encouraged. That helps making that decision on the interim. Secondly is BJ tapping on my shoulder saying that if you wait another year, you got Merck and Trenchmore, AstraZeneca launching, your commercial success is going to be more difficult. It's going to be more challenging. That also has to go into our decision-making. It was mostly about the actual events that we're seeing. That was the main reason for that. We didn't even think about an interim until we start seeing the events going down. So significantly. That to us was the key reason. I think, like I said, the most important thing again, of course, the alpha penalty, if you want to call it, is actually nothing for us. I just want to keep making that point. The actual study 0.01 is not impacted at all by the alpha that we have to take for the interim. There's no penalty at all for the interim analysis for the study. I want to make that point clear, that people bring that up as well. That's the other thing is I just want to bring out. I think we do have an extra roughly a year to launch, has an impact with the competitive landscape out there that we have to also consider. Yeah. I guess from a finance standpoint, as Michael said, when the trial was started, the company had a very different financial picture to where we are today. We have the ability to invest the year in, if we need to, just further preparing for a launch. It's having all those pieces in place. From a disclosure standpoint, once we're notified by the DSMB of their decision, we'll share that with you. Separate from that will be the actual number in terms of the MACE benefit. Again, we'll be as transparent as we have in the past. That's a policy that we're not going to change. Steve Tuch, Cantor. Just to follow up on the blinded event analysis. When you project the placebo arm that you were talking about doing from BROADWAY and maybe from the precedent studies, do you assume that itself slows down— Yes ...in year two and year three? Yeah. To what extent? Maybe talk about what is informing how you model that. Yeah, there is a decay you apply to the placebo arm also. There's different ways of looking at placebo decay. We have accounted for that in our analysis, yeah. Then you have an average. Three-point MACE decay is a lot less than four-point MACE. Four point. Yeah. We studied this very extensively, actually. AI is terrific. We have a lot of data that we could analyze for decay rates of placebo arms. Each study's different a little bit, but we even take more extreme examples. We feel we're still good on the blinded event rates. We've been extremely conservative in actually building worst-case scenarios, and even in those kind of simulations, we still feel very good. Yeah. Okay, thank you. Maybe this is for BJ or anyone who wants to answer, curious if you have any updated insight onto a pricing decision for Menarini or just maybe framing expectations of how this would be priced in Europe and trying to calibrate us for what to be modeling here. Yeah. I'd actually like to maybe introduce Steve and let the expert kind of respond to this. Don't get your hopes up because we're not going to share actual insights on that. What a way to meet you all. It's apparent what Ian just said, we're not going to answer any of those questions. It is really too early to speculate or put anything out there about where we see Menarini's pricing. I would just say, coming back to the commercial presentation that BJ led, when you think about the size and scale of this market, the opportunity to reach millions and millions of patients with a differentiated asset, that's what we're really super excited about. Without saying anything more, I'll leave it at that. Thank you. Very good. Hey, it's Leo from RBC Capital Markets. I just want to make sure BJ does get some air time here. I guess maybe a two-part question for you. I guess the team's obviously really excited about the ObEze combination, but in the survey you showed, it didn't look like physicians had a higher intent to prescribe. In fact, maybe it was incrementally lower. I guess, how do you square that? The second thing I wanted to touch on was Merck's label. They got a label that had no AE table, an implied CVOT benefit. I guess, how do you think that informs how you're expecting your label to look and ultimately how you maybe detail against Merck? Thanks. Sure. Sorry, if you don't mind, I'm actually going to pass that baton over to Serina to give her a little air time on this. Specifically around question number one. Question number two, I think I'll probably maybe hand it to Michael about the label just to talk about the relative impact on the label. Yeah. Yeah. Merck had a really good label. Yeah. That's great to see. I think it's good. Yes because that one will also carry over to us. Yes. That's one of the points we wanted to make is the labeling is getting more. Payers are using labels for restricting access, and that label, I think, for Merck is a terrific label. I give them a lot of credit for the label that they got. I think that obviously you hear what Amgen's going to do. They're going to hammer their outcome data. They're going to hammer the dosing regimen, the food effect, and all that kind of stuff. It'll be between Amgen and Merck and oral versus injectable and all the issues that go with that. We believe the very fundamentally different value proposition for obicetrapib. Again, we tried to show the on-treatment analysis today to highlight for you that our FDC with ezetimibe, we're in the 60% range also. We're in that same LDL lowering range with our FDC. I've heard this feedback from a lot of folks that Obi is a kind of a good utility Field, but not as good an LDL or not as good as Lp(a) lowering as the Lp(a) lowering drugs will be. I take that's potentially a little bit true. On the other hand, what I would say is that what Obi provides, take a look at the patient journey experience. Again, I speak from my own experience. When you prevent diabetes, when you lower Lp(a) without the injection, but in that range where your Lp(a) lowering therapies are not going to be available or not approved, and you potentially prevent Alzheimer's disease, that becomes a drug that instead of, I have to take this drug, they want to take this drug. I can tell you that for sure, that this is a drug that people are going to want to take as opposed to have to take because their doctor makes them take it. Those are the differentiations that no one else has. Again, I think it's going to be a great differentiator. Again, Merck is going to help grow the market. Yes. We're going to learn a lot. Yes the Merck launch that's going to help us a lot when we launch our drug. I'm looking forward to how that drug does. I'll be using it a lot in my lipid clinic as well, I'm sure. I know, Serina, I didn't want to take away your thunder. Yeah, I don't know if I can add anything. That's wonderful, Michael. Thank you for the commercial mindset in addition to your clinician perspective. The data that BJ showed, we actually have a number of different cuts looking at relatively similar in terms of their interest in using either the monotherapy or the FDC. In fact, some of our early demand studies actually show that we do believe that the FDC will primarily be used. Physicians, you get that innovation in Obi as the first-in-class new mechanism of action, potentially, that we'll see there. We've got the opportunity to add an FDC with an already trusted, well-known, tolerable option for individuals. This is that synergy that we start to see where other lipid-lowering therapies just weren't designed to do that. We think that that makes a very safe, effective, tolerable option that clinicians are going to be very comfortable with. Hopefully, that helps to address that question on the FDC. Maybe I'll start with a question for BJ. Sure. We know where the oral PCSK9s are priced. We know where the injectables are priced. When Obi launches, you'll have your outcomes data. Does that give you more wiggle room on the pricing compared to the oral PCSK9? I would say the following. Please correct me, Steve, on this one or jump in. We have to see, obviously, what happens with PREVAIL for sure. Is there opportunity for there to be some premium in that regard based upon the outcome? Sure. Right. I can say with confidence is that Merck, we're still watching what happens here, they came at 50%-ish or 40% reduction in terms of WAC compared to injectables. We're watching very closely in regards to rebate structure. Again, we don't think that they're doing anything to undercut the value in the market holistically. We don't see that as a negative at all for us. Steve, anything else you want to add? Okay. The only other thing I would add is just focus on the size of the market. I think as I hear your questions, it's really looking at the model and what kind of drives value. The biggest source of value is the sort of unlimited number of patients that are out there and the opportunity for us as well as other companies that are in the space to be quite successful. It's a point that you've heard from several of us today. This is not unprecedented. We've seen this in this market before. The opportunity in light of the labeling changes that Leo asked about, this is something that's been going on for two years now. We first saw the FDA expand label to include patients with really anyone with elevated LDLs, no longer restricting it to secondary prevention. We also saw expansion of sort of the MACE indication. I think it's an alignment of all the factors that we could possibly have to support a launch that's successful for all parties. That's what gives us really ultimately confidence in being successful commercially. As one of you wrote to me, BJ has probably one of the easiest jobs ever in commercial launch for selling a drug. We know that's true. No pressure. You'll do better than that. No pressure. You crush it, yeah. Just one more then for Michael and John. Given what we know from the HORIZON baseline and the difference in MACE, the endpoint, what does it mean for your interim if HORIZON reads out with a 12% risk reduction or fails? The CEO said that 13%-15%, he would consider a win. Why did you choose 12? Yeah. That's the stock score we did, and that's where the stock seems to be. That's why we said that. I think that a signal that for Novartis would be a disappointment in terms of its effect size would for us always be a win. We just want to see the principle. HORIZON for us, of course, I mean, for patients and for everyone would be fantastic if it would be 21 or 19 or 20, then all hands down. If it would be 14 or 15 and just not meet statistical significance or not enough so that there's a lot of discussion at the FDA and at the CHMP, it would be still good because everybody would expect after that Amgen would make the final goal. That, I think for us would be very good. Okay. Yeah. What we need from HORIZON is a biological confirmation. That lowering Lp makes sense. That's the bottom what you would want to see. Now, it's very different for Novartis and Ionis, of course, for science and. Yeah For NewAmsterdam, we just want to see that it makes biological sense. If I could add, please correct me, both of you. For PREVAIL to be successful, all we need is to reduce LDL by the magnitude we've already reported. The Lp is an incremental contributor, we've already shared with you obviously the outcomes benefit we saw in BROADWAY. The explanations might change, the reason behind the outcomes benefit from BROADWAY and what we could potentially see in PREVAIL. I just don't want you to connect those two dots, failure in HORIZON represents a risk— No To PREVAIL. It doesn't. Yeah. We never took any of that into account when we looked at PREVAIL. We look at PREVAIL, we look at numbers, the numbers are the numbers. There's no explanation as to why behind those numbers. We did it in BROADWAY because you can't control yourself. You want to do a mediation analysis of results. That's what everybody always does. There are some hypothesis-generating thoughts coming out of it that include Lp small particles and HDL, which is logical because that's what the drug does biologically. If you look at PREVAIL, you don't need that because you just look at numbers. As Michael was saying, the numbers give great confidence. Then we'll see. HORIZON, in essence, for me, just needs a biological kind of confirmation. That's it. I think we made this point before, but if you look at LDL, non-HDL, ApoB, just looking at those alone from our BROADWAY data imputed into PREVAIL, the benefit in BROADWAY, we're at 17%-23% relative risk reduction. That's without any other plus benefits. If you look at REVEAL, which is, that John tried to show, that 17%, if you adjust for how much more LDL, non-HDL lowering we'd have, we're in that BROADWAY-plus range on relative risk reduction. Those are two ways of looking at it. The other way, of course, is what we're seeing now live on the event rates and how we can— Yeah Impute a placebo rate into our blinded data and come up with numbers that look promising for stopping at the interim. At the end of the day, we don't count for anything. To Jas's point, why not go all the way? Go to the end. Go to the end, so we can get the relative risk reduction that's a positive trial. That's what it comes down to. Yeah. Maybe the one final factor is the operations of the study. I think we've shared this in the past, but we didn't do it today. Our clinical operations team has just done a phenomenal job. As we track metrics from a standpoint of new patients on therapy, dropouts, drop-ins and so on, we compare quite favorably. That's the other sort of unknown or factor that could play a role, and I think our team's done a really good job of managing that. We're doing way better. That's an understatement for we're doing way better than any recent other trial. Yeah. Yeah. Those are very thorough answers, I'm going to throw in two other questions. Our honoraries from Leerink Partners. Just stepping back, just thinking about all the historical CVOT data that you've leveraged so far, I was curious if you have any updated thoughts on some of the recent CVOTs that have missed, including ZEUS. Obviously, different drug, different target, et cetera. Are there any considerations we should think about framing that against PREVAIL and building your conviction there into the interim? A second question is just, if everything works out, let's say PREVAIL stops early for good efficacy, and you also have positive data in hand with RUBENS, how should we think about the implications for Obi and the FDC label and how physicians would interpret that? Shall I? Yeah, you want to. You do the second. What is unfortunate at this time is that, of course, if ZEUS is negative and there are discussions on the horizon, that people think outcome trials are not working. That's not good for us because we have an outcome trial around the corner. That's a very muddied discussion. First of all, ZEUS simply did not answer the null hypothesis. I have not seen a single tweet. I know it's not called tweets anymore. I haven't seen a single tweet or heard a single podcast that gave me any reasonable explanation as to why this happened. Basically, no one knows. It's truly you have a null hypothesis, the trial's completely negative, 0.99. Everybody's flabbergasted. Peter Libby held grand rounds at Harvard Medical School one week ago. Sanjay Kaul wrote me a tweet. He said, That did not mature well, because one week later, the trial was negative. Even the brightest minds on inflammation did not see this coming. We can certainly not see this coming. It's a separate entity. HORIZON we've already discussed. I think both HORIZON. Definitely ZEUS has nothing to do with PREVAIL at all. The null hypothesis for CETP inhibition is already answered by PREVAIL and the Mendelian randomization studies and everything else. There are four Mendelian randomization studies showing that low CETP leads to less heart attacks. We're not worried about PREVAIL being positive. The real issue is how positive, of course. HORIZON, I think we've already discussed. Those are very different things, but sometimes people heap them, and then it becomes, of course, negative for us, which is a bit uncalled for because one has nothing to do with another. Well, I'll add a little bit because obviously, this was very disappointing. I do think we'll have to wait and see what the data tells us. It was a pretty sick population, and I think that's one of the key things about all these trials is that you have to treat the population with the modifiable factor that can still make a difference. Like you said, Alzheimer's is another good example. If we had started using lipid therapy for heart failure reduction, we never would have seen a benefit. That's the point. You can't go too late. I'll have to wait and see what ZEUS says, but I have a hunch. We know it was a sick population, a very high event rate, very high mortality rate. It just could have been too late for the population to benefit. We will have more with the Artemis and Hermes to come. It's unfortunate for the field. We'll have to wait and see what the data is at the American Heart. To your other point about the diabetes RUBENS study, we're very excited about it for a couple of reasons. One is that it is a prime differentiating population for Obi. Again, talking about my experience in the clinic, patients are definitely afraid of statins causing diabetes. That's a known effect. In fact, a paper just recently came out that the risk of diabetes goes up 25% when you're on high-intensity statins. Patients come to you, they're using AI just like we are, and they know that statins cause a high risk of diabetes. Obi has that benefit. Again, it may not be in our label that prevents diabetes, but the RUBENS study, what it presents is an opportunity to show how well the drug works in the diabetic patient and the label of not just those with heart disease, but those without heart disease. As you know, that's the VESALIUS population benefit is quite dramatic in that population. As we believe that's a population to focus on for, quote, primary prevention that's very large. We see this as a chance to get into that broader population in our label with the RUBENS study. Also, just the good fortune that Obi works better in diabetic patients than it does in non-diabetic patients. So we have another chance to get an LDL-lowering— [inaudible] ...benefit that's in our label that it's higher than what we have already. That gives a chance for BJ and his team to promote that. Those are all, I think, real positives for RUBENS that we'll see relatively soon. Hey, guys. Sorry, I'm kind of hiding over here. Matt Phipps, William Blair. Thanks for the great presentation. You outlined a number of events that you expect the primary to be greater than 950 for MACE 4. What should we expect for MACE 3, 60% of that? With the lower event rates, should we assume there's a greater alpha spend to hit that MACE 3 just given the lower events rate to accommodate for that? Thinking about the timing of an NDA filing at this point, is the options really either maybe mid-next year with a positive CVOT included or later next year knowing the review is going to happen during the full primary readout, which would be available during the review? Thank you. Matt, we're not going to give the exact numbers, we had those greater-than signs on purpose. We had two greater-than signs before the 950 at the interim, just so you know. It's going to be quite a bit more than what we had at the initial study readout for both three-point and four-point, obviously. we can't give you the exact numbers because people reverse-engineer, and you start getting all kinds of questions about relative. we can just tell you what we're telling you, that we feel good about what the interim is going to show for both four-point and three-point. Again, a BROADWAY-like benefit for both three-point and four-point. We're safely in the P values that we need to stop the trial. we need it for both three and four-point to be consistent with each other for that reason. that's almost always the case, by the way. If anything, three-point is better than four-point. VESALIUS was better, 2025 versus 2019 or something like that for— The alpha spend doesn't matter. The alpha spend doesn't affect us at all, actually. Doesn't affect us at all. No. Not for the three-point either. Yeah. Can I take the question on regulatory filing? Right. Okay. Yeah. Don't want to forget that question. Our plans haven't changed, and this is informed by engaging with payers. What they want to see is outcomes data. They want to know the outcomes data. The idea of waiting for the outcomes data to file, that's not something that we're considering today. Related to that is we're obviously engaging with regulatory agencies, and specifically the FDA, to file at the earliest possible date. We don't want to delay the filing as a reasult delay the launch. We're obviously mindful of when the outcomes data will be available as a result in the public domain. Those are the things that are going to inform the overall timelines. It's not a complete answer. I'm sure it's not a very satisfactory answer. We'll do better. Hi, this is Krupa from Truist. Thank you so much for the very detailed presentation, and John, definitely not boring. I actually wanted to switch gears a little bit and ask about REMBRANDT. With enrollment complete right now, just was wondering what to expect over the next few months. Could we see any interim or blinded data? How confident are you that the changes that you see in the NCPV will translate into clinical benefit? What magnitude of benefit would you have to see with the regression to see benefit in CVOT? I also saw that you're measuring FAI. Was just wondering how you expect that to play out. If you see benefit in both FAI as well as the plaque regression, what does that say about Obi in terms of maybe impact on inflammation? Thank you. I think I have to start a little earlier on the mechanism of Obi and ezetimibe. What we saw in the animals first and later in our phase III program also, is that the two mechanisms are actually more than additive. There is a synergy between inhibiting CETP and inhibiting cholesterol absorption in the gut. If you look in the animals, that led to astounding regression of severe plaques and astounding regression in the aortic root surface area. What happened in the animals, if you give the animals, which is the best humanized mouse model on the planet, is the ApoE*3-Leiden CETP knock-in mouse that every major company uses that wants to study their anti-lipid drug, is that you basically eradicate severe lesions. That goes almost always hand-in-hand with a very severe lowering of the FAI. Those are two effects that are not totally separate from one another. I think that, and I am not a cardiologist, but I think that in the cardiology community, we are getting pretty close to CCTA being approved by the regulators as an intermediate biomarker that aligns extremely well with outcomes. Of course, behind the scenes, there are major institutions in the United States who are working towards that. I have great hopes that because we are testing not only Obi mono, but we are also testing the fixed-dose combination in REMBRANDT, and we have seen the goal attainment if we do on treatment, and we've seen the LDL lowering and all the other benefits. Then we have the preclinical work. We have great hopes that we'll see very large effect sizes in that trial. 18 months is the right time. I think there are some 12-month studies, but I think 18 months is a better time course. We're using the technology that was literally last week approved by the FDA and the company Caristo, is a company out of Oxford again, from a Greek professor of cardiology who has developed his whole career based on the FAI. I think it's a bit difficult to discuss this in relation to ZEUS because the FAI shows you pericoronary inflammation as one of the most important determinants of risk. We've just seen that lowering IL-6 actually doesn't do anything. The FAI predicting risk, I think, is a scientific data that has no question. I think what we've done is we have the drug that lowers the parameters that we want to lower to a very large extent, PCSK9 like. We've shown in animals, the most relevant animal model, that we eradicate non-lipid plaque and inflammation. Those data are still to be published, by the way, so we are going to publish that. We are now using the most validated technology in the patient population, and I can say one thing is that baseline plaque in those 323 patients is more than enough to show a difference between placebo and intervention patients. Actually it's my favorite trial right now. Yeah. Other than PREVAIL. Yeah, of course. After PREVAIL. I want to emphasize one point that John said. We do know the plaque levels are high. That was the difference between other recent trials for using non-calcified plaque volume. We specified. The Ionis trial had very low plaque. A high level of plaque at baseline, which is right in line with our expectations. Speaking as a cardiologist now, the whole field in cardiology is changing to look at these imaging modalities, clearly HeartFlow now, by Caristo. The future really is changing plaque before you get to events. Remember, we think it's going to be a landmark trial because I think we'll be the first out there to show a benefit for LDL lowering, especially with the combo. I think we're head of VICTORIA. We're the lead on that. Yeah Study. Cardiologists love this imaging, like the [Helton trial] that Amgen had. It's not on their label, but they promote it with their reps, and it's very well-received by cardiologists. Before VESALIUS, it was one of the big drivers of growth, was having those imaging studies showing a regression of plaque. Yeah. We think that's going to be a great value add for Obi with having the REMBRANDT study in our label, or in promoting as well. They like images. Yeah, right. They like seeing things get better. It's harder to name them. Yeah, right. Hi, it's Anne van Lint from Kempen. I have two questions for you. Can you share some insights from your discussions with the FDA on the SPINOZA trial? Do you think that p-tau can potentially be in a future label for OB, and what will the timelines be for this trial? The protocol was reviewed by the FDA. It gave us the green light. Not getting too far ahead of the design, because we want to come out with a big splash on this. They do like p-tau. They're not quite ready to approve a drug based on p-tau. As John said, we're getting there. Getting there. A lot of advocacy going on among, especially the APOE4 patient community. They're fine with it being an endpoint. We are doing cognition as well in the SPINOZA trial. The point is that we don't think approval can be based on SPINOZA, but we do think it'll lead to a very important follow-up study. I mentioned this message about we have very good data on if you have a high p-tau and you're E4, your progression from normal to mild cognitive impairment is 15%-25% over five years. That's better than a MACE of that rate. Yeah. We can actually do a reasonable study. Yeah within five years to show prevention of Alzheimer's. Let's say they already have Alzheimer's disease. Let's keep that clear. They already have Alzheimer's disease. Prevent the conversion of normal to abnormal cognition in a reasonable period of time, at a reasonable cost. The FDA has approved the study, they want to see the spectrum of risk patients in that study. We'll announce that within the relative near term when we start the trial officially. Thank you. Maybe one more question for BJ. Next to LDL-C lowering and MACE benefit, are there any other factors that you think will be important for the uptake, and what do you think you'll get in the label? Yes, in terms of the items around residual risk that we talked about, those we think are actually very important. Michael and John specifically have spoken about Lp(a). Again, small particles, the rate of onset diabetes. Each of those things have been reflected even in our demand study in terms of importance for prescribers. There's a relative input in that. In terms of whether we think they'll get in our label or not, I actually don't want to comment on the probability of that. Let's just say we're doing everything we can to include as much as possible in the label and create data that allows us to be consistent with labeling. Michael, would you like— Yeah, I just want to add that the AI world is changing everything dramatically. Label or not label, I really don't think it's going to matter that much pretty soon. Doctors are going to use AI to determine what the right drug is for a particular patient. That's why we're a publication engine. Yes. We want to generate all these papers that gets into the AI sphere. Algorithms They can generate data. The more we can do that, the more we're going to get the information out there for clinicians because it's a changing world. It's changing very rapidly. The genie's out of the bottle already when it comes to how doctors are using AI for getting their information. It's going to change everything that we do. We hired a full-time AI person about a year ago, which helped a lot with PREVAIL assessments and even helped design SPINOZA, how we design trials and how we go about looking at our data. It has been a tremendous benefit already, I think a lot more to come when it comes to how we even launch the drug and how we communicate information to clinicians and to patients. We're going to see a huge difference in just a few years about how information is circulated to all our stakeholders. We're trying to be cutting edge on that as well. Great. Thanks for all the very helpful color. Yanan Zhu from Wells Fargo. A question on the MACE 3. I think you mentioned if PREVAIL replicates or show a similar MACE 3 as BROADWAY, you should be okay for the interim, right? I was wondering, could you remind us the MACE 3 benefit, and the definition of the MACE 3 from BROADWAY? There could be some changes between the MACE 3? Remember, well, MACE-3 was in the right direction. It wasn't the same magnitude because of the stroke in the wrong direction. Again, one year is not the right thing for MACE-3 particularly. What we're saying is we have a MACE-3 across all the trials, is that we have MACE-3 is the easiest one to compare across trials. It's non-fatal MI, it's CHD death or CV death, and stroke. Okay, those are relatively easy to compare across trials. What we're saying for MACE-3 and for the stopping, we want to see the MACE-3 being the same type of reduction that we saw with MACE-4 in BROADWAY, is what I'm trying to say. That's the point I was trying to make. In other words, that 21%, as I try to say, we have some wriggle room there, too. It doesn't have to be 21%. It could be less than that. We're not going to say how far less, we have some room to move on the MACE-3 as far as our powering is concerned right now. What we've said already publicly, too, is that the event rates are down. We're imputing a certain placebo rate that we can carry forward from BROADWAY, even with decay, into the blinded MACE-3 event rates, and we're encouraged by what we're seeing. Again, we can't use the BROADWAY one-year MACE-3 data. That doesn't help us, other than the event rate itself, the MACE-3 event rate in BROADWAY, how we carry that forward year after year two now, and we're getting close to— Year three We're in year three now, we see how the events are tracking down, and we can make assessments about when we have the interim analysis for the number of events that we have, our MACE-3 total, we impute a certain placebo rate. It looks encouraging is what I'm trying to say, at that point. I think what's very important when you guys write about events is that you imagine how it goes these days. You're in a city like this, you get chest pain. You call 911. You're rushed into an ambulance, Door to balloon time is two and a half to four and a half hours. You get a stent. You prevent a non-fatal MI, you prevent a fatal MI. That's the first event that occurs. If you look in the timeline in trials, in BROADWAY, by far, the first thing that happens is you prevent PCIs, because that's the first thing where your therapy has an effect on. It takes longer to prevent non-fatal MIs, even a little longer to prevent fatal MIs, that's later, and even longer than strokes because stroke arteries are three times bigger than coronary arteries. For lipid lowering to have an effect on a stroke artery, it simply takes longer time. When you understand that that's the sequence of events, you also understand that if you look at four-Point MACE in a one-year trial, you are going to be positive because the vast number of events that you prevent are PCIs. If you look at two years, you have an effect on all the events, the smallest effect on stroke. Actually, if you go over the two years, everything catches up, then generally speaking, four-Point MACE is at its peak, and three-Point MACE is actually getting close to it. Actually, very often these days now, the effect, the percentual effect on three-Point MACE is better than on four-Point MACE. Look at VESALIUS, 19 versus 23, I think, or 24 or something. That's the reality of the new. In the old days, you had chest pain on Monday. You went to your cardiologist on Friday. The chest pain was gone. He thinks, Well, let me give you a stent anyway. It's good for my wallet, so I'll give you a stent. That didn't prevent any heart attacks. Practice has really dramatically changed. That old thing, in Europe, there's no reimbursement anymore for a stent that is not what's called ischemia-driven. Patients do need some sort of complaint before the insurance companies pay you for a stent. That's Yeah. Great. That's super helpful. I just wanted to clarify. Sounds like the alpha at the interim is 0.01. Is that the sum of the two, MACE-3 and MACE-4, or how to think about the interim split? Sorry. That is for MACE-4, but for MACE-3, we have a different P-value requirement. We are not saying what it is, but we have a different P-value requirement for MACE-3. Again, it's a secondary endpoint. We don't have to be 0.01. Secondary For the secondary endpoints, yeah. Okay. Got it. Thank you. Matt, do you want to say anything? All right. I think that's all we have time for on the questions. Okay. The team will be around for a few minutes more. We also have lunch available for people in person. Want to thank everyone for coming today. I guess, Michael, any final comments? Thank you again for coming. We're happy to keep engaging with everybody over lunch or socially here. Please stay around. I think we have lunch, right, outside? Okay. Perfect. Okay, thanks everybody. Thank you.