All right. Good morning, everybody. Welcome to NewAmsterdam's R&D Day. Thank you for everyone to show up who's live here, as well as everyone who's on the webcast. We have an exciting day planned for you. Let's see here. First, you know, we may be making forward-looking statements today, so please, everyone, pay attention to this slide. Just to kind of give you a brief overview of what will be discussed, we have a good number of the team here. We have Michael Davidson, who will give us a brief corporate update, obviously go over a little bit of the recently announced Alzheimer's progress that we've announced, as well as provide some PREVAIL updates. John Kastelein will follow him up, really walk through our BROADWAY analysis. Really, you know, one of the key points that a lot of investors have is, you know, let's walk through MACE and the MACE benefit and reduction that we saw on BROADWAY and help understand that. Then we will move it over to BJ for a commercial update and really discuss the market opportunity and where we see obicetrapib and NewAmsterdam moving from here as we prepare for our commercial launch. With that, I'll turn it over to Michael to kick things off. Michael. You know, thanks, Matt, and good morning, everyone. It's an exciting time for the company, and we are really pleased to have our second R&D Day. I know many of you were here last year, and we got great compliments. Some people said it was the best R&D Day they've ever seen. This is something we're going to try to outdo last year in regards to the information provided about the company. So 2024 was, by all measures, you know, a stellar year for the company. We completed our three phase three trials: Brooklyn, Tandem, and Broadway. We built out our tremendous commercial team. The medical science liaisons have been deployed and getting great feedback and relationships in the medical community. We are almost 100 people, and we have three offices across the U.S. and in Amsterdam. We also had a very well-completed financing, and now we have the capital that we need to bring this drug to patients through commercial launch. We also had, of course, some other important things I want to point out. We got the new composition of matter IP, which has been extremely important to getting us exclusivity through 2043. We had our data published in the New England Journal of Medicine for Broadway, and Tandem was published in Lancet. Very excited to see the medical community embracing the quality of the data that we had generated with obicetrapib. This year, of course, another exciting milestone is yet to be accomplished. The one, of course, we're going to talk about a little bit today is the exciting announcement from the AAIC that we will be a late breaker presentation on July 30th, where all data from Broadway will be presented, and we're looking to publish that as well in a leading journal. We also have our EMA filing second half of this year, and of course, the study ongoing called Vincent looking at PCSK9 inhibition in combination with obicetrapib, especially focusing on the Lp(a) additive benefits. That's our hope with that trial. Here is what we call our rainbow or umbrella about what obicetrapib provides to patients. One of the great joys for me, being a clinician and still seeing patients and recognizing how important not just one aspect of a drug is, but the totality of that drug's benefits to patients and tolerability. For obicetrapib, we could not have been blessed with a drug that can provide this range of benefits so effectively and, based on our phase three trial, so well tolerated and safe. We look at this all the time and try to evaluate ways we can keep expanding how this drug can provide greater benefits to patients. You're going to see this throughout our presentation about how important the LDL+ is for us, for both our patients and our way of developing the science around obicetrapib. Alzheimer's, for those of you who know the company from the earliest days, this was a focus for John and I. When we came on board, we had been working already on HDL raising as a pathway for treating or preventing Alzheimer's disease. We begged for a little bit of funding from our investors to allow us to do some work in Alzheimer's, and we're grateful that they were able to do that for us. We'll go through some of the continued milestones we've had on the last five years for developing this important added benefit of obicetrapib. Multi-infarct dementia is addressed by LDL lowering. Statins have well-documented reduction to stroke, and now all the new trials for LDL lowering have demonstrated a stroke benefit for LDL reduction. That is something that obicetrapib provides potential benefit through its LDL lowering effects or small particles or Lp(a) and so forth. For Alzheimer's disease, it's a much more complicated situation. We know that LDL does not link up to Alzheimer's nearly as it does for multi-infarct dementia. We know that statins in a large trial had no benefit on treating Alzheimer's disease. We are very, very grateful that we are able to pursue the benefits of obicetrapib, which is beyond LDL lowering and predominantly focusing on HDL raising, can have a benefit on the treatment and prevention of Alzheimer's disease. We'll go through the rationale for you in more detail. One of the important aspects about lipid metabolism is that the brain is by far the richest organ in cholesterol. It's only 2% of the body mass, but yet has 20% of the body's cholesterol. The blood-brain barrier and the rest of the body make the metabolism of cholesterol totally separate. They're not connected to each other by any direct mechanism. It's always been interesting why this separation occurs. In fact, it's been proven that when you give somebody a liver transplant and you give them a new liver, the cholesterol ApoE4, if the liver isn't the four, will not be ApoE4 in the brain. It'll be different. It is totally separated from the rest of the body. This cholesterol is very important for brain development. It's involved in making myelin. It's involved in glial cell and neuron stability. It's a very important part of the normal healthy metabolism of the brain. There is no LDL in the brain. It's only HDL and ApoE. The theory behind what we've tried to develop with obicetrapib is that HDL is the one lipoprotein that interfaces with the brain and is there to transport nutrients to the brain and export oxysterols, 24 and 27 hydroxycholesterol, which are the metabolites of cholesterol in the brain. These metabolites of cholesterol, we now know, are very important in the amyloid beta plaque formation. By maintaining healthy cholesterol balance through HDL raising, you may have a major impact on reducing the amyloid and tau pathology that occurs over time with Alzheimer's disease. Another point is that the turnover of cholesterol is so much slower in the brain than it is in the plasma. You need a vehicle to be available to remove cholesterol as needed to reduce these excesses that can ultimately lead to the pathology that we see with Alzheimer's disease and other neurodegenerative diseases. Here is just a little bit of a closer look about how cholesterol in the membranes facilitates aggregation of A beta peptides into amyloid plaque. We kndow that HDL is involved in clearance of Aβ peptides and therefore may be involved in preventing progression of Alzheimer's disease. We also know that Alzheimer's is characterized by amyloid and plaque in the CSF and brain. Now, with excitement, I think this really exciting progress in developing biomarkers that can actually measure these important disease effects of Alzheimer's in the plasma, like amyloid and tau, especially tau-217. ApoE4, this is an important gene not just for Alzheimer's disease, but also for heart disease. ApoE4 carriers have about a 22-45% increase in cardiovascular disease risk. Their LDL levels are higher. Their HDL levels are lower. Their Lp(a) levels are elevated. Just this one amino acid difference has a tremendous effect on adverse lipid metabolism in the brain. They exhibit decreased cholesterol transport, lipid accumulation, Aβ aggregation, and we believe impairment of clearance of cholesterol from the brain. As I think many of you are aware, it represents roughly a quarter of the patient population have ApoE3/4 or 4/4, but represents two-thirds of all those with Alzheimer's disease. It is a very important gene for Alzheimer's disease, but also for cardiovascular disease. This has been, again, a target for us from the earliest days of NewAmsterdam Pharma. Can obicetrapib with HDL raising be an effective therapy to prevent Alzheimer's disease, especially in ApoE4 patients? In ApoE4, putting on my clinical hat again, I would say, because I check ApoE4 in all my patients, and 23andMe was doing it for a while also, when people find out their ApoE4, it has a very significant impact on what they want to do to try to prevent Alzheimer's in the future. We know that for those that have 4/4, for example, almost 100% will have Alzheimer's disease by age 90, if not earlier. In fact, usually you start seeing evidence of cognitive impairment in your 60s and 70s. It is a very severe late-onset form of dementia. E3/E4, usually about 10 years later, and then E3/E3 about another 10 years later than that. You can see that when someone has E4, they're highly motivated to think about options to reduce their risk of Alzheimer's. We have things that we recommend: exercise, great lifestyle, DHA supplementation, things like that. However, we know ultimately that we do not have good evidence that anything works. We know also that the anti-amyloid therapies not only are not as effective for ApoE4, especially ApoE44, but also have an increased risk of ARIA bleeding in that patient population. A major game changer in the field has been the p-tau-217 biomarker. I want to share this with you because we saw this data and we recognized that we had an opportunity to look at our Broadway trial with 12 months of therapy in a very large set of patients who we knew many of them would be ApoE4 just by the fact that these were atherosclerotic cardiovascular disease patients. Now, the challenges that we face with this biomarker is that you see that it's pretty flat, very, very gradual increase over the decades, but as soon as you reach about age 65 or 70, that biomarker, which is disease itself, it's the p-tau in the brain that's leaking out in small amounts into the plasma. It really is a marker of the disease itself, does increase exponentially. We weren't really sure how much we would see an impact in just 12 months. As we announced just on Monday, we were very excited that we did see that benefit in the overall population and also even more prominently in the ApoE4 population. Here's E4. You cannot ask for a better biomarker for both sensitivity and specificity for predicting the conversion of normal to MCI, mild cognitive impairment, mild cognitive impairment to Alzheimer's, then progression of Alzheimer's. This biomarker works beautifully as a predictor of those important transitions in patients that have risk for Alzheimer's and then transition to Alzheimer's. It is going to make a big difference in how the disease is diagnosed and, of course, how to monitor therapy and therapeutic effects of different options and different therapies. Because it does, as I mentioned, it evaluates the disease itself. You look at the correlation between the plasma p-tau-217 and the tangle densities on PET scanning, they are highly correlated with each other. It is an excellent biomarker. You can see the news about it just recently that it is going to be part of patient care. Again, for me, clinically, I am doing it already in patients. A number of labs offer this test, and it is going to be very, very helpful initially at making the right diagnosis, but also as a way to track disease progress and treatment benefits. Okay, what have we done with obicetrapib? To go back again to the rationale about why we're so excited about obicetrapib's benefits on the prevention of Alzheimer's disease. The fact that we do have BROADWAY with 3,000 patients with a favorable safety profile, and we measured in a small study 13 patients that had ApoE4 and mild cognitive impairment. This is prior to p-tau-217 being available. We saw significant reductions in 24/7 and 24-hydroxycholesterol in the CSF. We also saw, and we've presented this data, marked increases in lipophilic antioxidants and carotenoids in the CSF correlating with the plasma increase due to HDL raising. Again, this confirms that the plasma increases in antioxidants that we saw with obicetrapib were directly correlated with the amount in the CSF, which means that the HDL must be transporting the antioxidants into the CSF. Again, a confirmation that we are, in fact, modifying the CNS metabolism with our HDL increase. We saw stabilization of Alzheimer's markers in this small trial, but we also saw some phenomenal clinical benefits in a few patients. We are very, very encouraged by this pilot study and decided what will we do next. We met with a very prestigious group of Alzheimer's experts, and they recommended that we go forward with further studies, which I'll get to in a minute. We also did our own funding of research to further confirm the Mendelian randomization data that was first seen in 2010, published in JAMA, that when you have CETP loss of function and also ApoE4, it mitigates the risk substantially. This was also noted in the Bronx Aging Study that one of the most prominent genes for longevity in the Ashkenazi Jewish population over 100 was a CETP loss of function. This was, again, further confirmation when we did the U.K. Biobank and other larger studies. We're talking about millions of people now. We saw the confirmation that the CETP ApoE1 increase, HDL increase, was correlating with reductions of different forms of dementia and more so in the ApoE4 population. Let me walk you through some of the preclinical data that really got us supercharged about what to do with obicetrapib. One of our colleagues, Lisa Munter at McGill, had noted—this is, again, going back five years ago when we first started NewAmsterdam—that when you knock in CETP into a mouse who do not have CETP, you increase brain cholesterol by 22%, and you also increase the pathology of Alzheimer's disease quite remarkably in an APP also knocked in. Those are the amyloid precursor protein knocked in with CETP together, got much greater amyloid and tau pathology in that model. Then she went forward and looked at what happens with what correlates with what's called the NOR, which is the recognition, the cognition. HDL raises would improve cognition, LDL lowering would decrease cognition. When you knocked in CETP. She then gave the animals a CETP inhibitor, obicetrapib, and that improved cognition in this model. They're able to do appropriate nesting, which is the measurement of cognition in this animal model. Very exciting data, preclinical data saying that you can, in fact, CETP is very bad for promoting Alzheimer's pathology. Using a CETP inhibitor can offset that disease pathology very effectively. Now comes our Broadway data. Again, we decided that we could look at this study over 12 months and evaluate in everybody that we could Alzheimer's disease biomarkers. The most prominent being, again, p-tau-217, but also other biomarkers, the ratio of Aβ42/40, GFAP, NFL, and an older tau called p-tau-181. We were able to basically get the majority of patients in the trial at a baseline obicetrapib before obicetrapib or placebo, and then look at the one-year mark for a second sample to look at both a baseline and a 12-month sample of these different biomarkers over that 12-month period of time. As we announced on Monday, this has been accepted for an oral presentation in the developing topic session. Also, we are very grateful that the AAIC themselves put out a press release saying that NewAmsterdam is incredibly promising data on the future of combination therapy to address all aspects of disease, considering the benefits on reducing progression of Alzheimer's disease with these biomarkers in the course of disease in this study population. Like we said, we feel this is an extremely important part of another benefit of obicetrapib that we want to further evaluate going forward. What does that mean for our rainbow, our umbrella of benefit? We'd like to add now ApoE4 into that umbrella, which is 25% of the population. I can say, again, speaking as a clinician, nothing is more motivating about doing lifestyle changes or taking any optional therapy that they can when they have ApoE4, because almost all of them have family histories of Alzheimer's disease. What I want to point out is not just a benefit that's unique or differentiating about obicetrapib, but it's the urgency to treat or the desire to treat that really is important about this drug's profile. Alpila is another example. Leading referral to my clinic, self-referral even, is high Lp(a). They want to know what they can do about it. We know that we have therapies on the horizon, but obicetrapib can be—we'll hear more about that from John about how obicetrapib fits very well into the Lp(a) lowering landscape. This becomes a drug that can be an exceptionally good companion to any other LDL drug, especially statins, as we talked about before. Statins raise Lp(a), obicetrapib lowers it. Statins raise the risk of diabetes. Obicetrapib lowers it. Statins don't lower small particles. Obicetrapib lowers small particles dramatically. Statins have not shown a benefit in reducing Alzheimer's disease. Our hope is that obicetrapib could be that option for those patients that have ApoE4. This is an exciting time for the company, and we really look forward to sharing more of that data in July when we have the presentation in Toronto. Now, to move on, I want to talk about PREVAIL. That study with our fantastic team is going exceptionally well. I mentioned already the publication. This is, again, just highlighting how important obicetrapib is to the medical community, published in New England Journal of Medicine and then The Lancet. I'll just read a few of these comments. I hope I can read them from here. You can see the comments from the different key opinion leaders that I think it's worth pointing out. If we already have the effect of LDL and ApoB lowering non-statins, I'm particularly impressed with the impact of small LDL particles, Lp(a), and new-onset diabetes, which is unique to obicetrapib. Obicetrapib could be the future of LDL lowering and could potentially replace PCSK9 inhibitor monoclonal antibodies, given the beneficial effect it demonstrates on other lipoproteins beyond just LDL and ApoB reduction. The magnitude of Lp(a) reduction in Brooklyn, Broadway, in TANDEM could get patients with very high Lp(a) levels into the normal range. This is a huge advantage of obicetrapib that other existing LDL lowering agents cannot achieve. If the MACE benefit in PREVAIL follows the early MACE benefit shown in Broadway, there is no doubt obicetrapib could be positioned ahead of all other non-statins given the exceptional tolerability and oral route. You are going to hear more from our tremendous Chief Commercial Officer about how this type of data, how attractive it is to the medical community based on our own research. Moving on about PREVAIL. Again, from the beginning of the company, one of the things, one of the value adds of having John and I in the leadership position is we've seen so many studies. We've been involved in so many trials. We've known the failures and the successes. That's an important thing about how to plan for these trials appropriately. A lot of things had to be learned the hard way, learning about studies. When you didn't anticipate that you needed to have—it kind of makes sense now, but believe it or not, it was not as evident in the past. In other words, to lower LDL, you have to have a high LDL to begin with to show a benefit. If you want to lower LDL, you got to have a long enough period of time of treatment to have a benefit. Those were, believe it or not, not really implemented as well as they should have been in many of these trials. The learning from that is to have the best success, you want a higher absolute LDL, and then you want to maximize the duration of the trial, targeting the right high-risk patient population that we know achieve the greatest benefit based on the profile of the drug. That is how we designed PREVAIL. We designed it not as a very large low LDL population that had to have a quick event rate to get available for the market, but rather we had the courage to start PREVAIL at the same time as our other phase three trials, all our other phase three trials, knowing we didn't have the money to finish it, but we thought we had the confidence that we could have enough excitement about obicetrapib that we could fund these trials to completion. We're gratified that we were able to do that to achieve the financing that we were able to do to now not just complete PREVAIL, but also the funding we need to launch obicetrapib in the marketplace. Also, the benefits that the drug has on the LDL plus side of things, those will all be evaluated in PREVAIL to try to understand what we've already seen in BROADWAY is this early benefit and this benefit that looks to go beyond just LDL lowering. We hope to have that type of analysis from PREVAIL to further enhance the belief about this very much a mechanism of action that goes well beyond just LDL lowering for cardiovascular risk reduction. John will go into more detail about that in his discussion. Here's another important thing about how we set up the trials is that we wanted Broadway to be as close as possible to PREVAIL to make people even more confident that Broadway would be a mini PREVAIL, that the benefits in Broadway and what we're achieving in Broadway would therefore give greater confidence that PREVAIL has the right patient population, the right design to achieve these benefits. We're very gratified that we achieved that objective. As you can see from the differences in the baseline lipids, they are almost identical, LDL 98 for Broadway, 103 for PREVAIL. Can we design PREVAIL to have a higher LDL at baseline? We enriched the study based on other trials where CETP inhibitor like anacetrapib worked the best, low HDL, high triglycerides, cardiometabolic risk. Those were all enriched in PREVAIL. Again, we saw that in Broadway as well, that in those patient populations, we saw even greater LDL benefits. We have a very, very good read-through from Broadway to PREVAIL on the baseline criteria. Just to kind of highlight here, we're showing you, I think this is for the first time, highlighting the comparison of Broadway to PREVAIL. You can see they're almost identical: age, sex, region, race, and so forth when we look at the comparison on the demographics. Then we look at the BMI, the diabetes%, the statin utilization, the other drug use. We're seeing a very, very, very similar profile. We're also gratified we're seeing very little drop-ins to PCSK9 therapy, little drop-ins to GLP-1. Compliance has been excellent. Dropouts have been low. The quality metrics that we're tracking are really stellar for a trial like this. Our event rates are on track to complete the trial, the patient part of the trial, by the end of 2026, the two-and-a-half-year mark that we had set as our goal for both event rate-driven and the time horizon. It looks like they are going to sync up pretty closely to what we were hoping for. Also, I know there has been a lot of questions about what we are going to do about our MACE selection, our composite MACE. We have done a lot of thinking about this too. Honestly, we are going back and forth about this ourselves internally about three-point MACE, which we saw in BROADWAY was our best relative risk reduction. It was also what was best in the REVEAL trial with anacetrapib. That was leaving out stroke. Stroke was not a positive benefit in BROADWAY. It was relatively neutral. It really only had less than 20 strokes in the trial. We did a lot of investigating about stroke in particular, especially ischemic stroke, which is what's LDL affected, not total stroke. With ischemic stroke, we looked at every single trial over the last decade and even more so. What we found was that for stroke, there was not a single trial in which the separation of the curves for stroke did not happen until after year one. There was no separation of the curves until after year one for stroke. Stroke just takes longer for separation. When it does separate, the benefits are as good, if not better, than any other endpoint in these trials. It is still a very important endpoint. It is also very important for Europe. They insist on the three-point MACE as one of the important composites. We'd have to have this data anyway. Also, with our Alzheimer's data, we want to be able to discuss—this is our aspiration—that we can discuss both ischemic dementia-related, ischemic stroke dementia-related, and also now Alzheimer's-related, both being prevented by obicetrapib. The other thing that's important is the FDA has modified their labeling and now they're harmonizing it with the cardiorenal. The endocrine division is now harmonizing with the cardiorenal division. They're allowing in the indication all your composite endpoints for that indication. In the past, they've limited your indication to what you saw for each of the composites individually. For example, Repatha did not have an indication for CHD death because it was actually a little bit above one in the trial. Now that's been relabeled to include CHD death in the indication based on this new guidance. Including stroke for us makes a lot of sense. Now we're going to go and confirm this with our academic steering committee. We will likely move forward with the four-point MACE, which is CHD death, non-fatal MI, non-fatal ischemic stroke, and total coronary revascularization. It gives us well-powered for that 20%+ benefit that we're expecting in the PREVAIL study. That's announcing that officially today because I know people are asking about that question quite a bit over the last several months, ever since the BROADWAY study was released. Okay. We're not going to take any questions yet because I think we're going to have a panel afterwards. I'm really excited to bring up my brother by a different mother and my close friend and colleague, co-founder, to talk about obicetrapib and cardiovascular events. Thanks, Michael. I'm older, so it's more like his father, I think. Before I take you back to heart disease, let me say a few words in general about CETP. The target of obicetrapib is the CETP protein. Obicetrapib 10 milligrams inhibits the activity of that protein by 97%, which is basically knocking it out. The first question that as a doctor you ask yourself is, are there any examples in nature where there are people that have basically no CETP from birth? The answer is yes. They live in Japan in a province, hundreds of them. What do they look like? Is there good literature about them? Yes, there is. There's actually a lot of literature about them. The two most remarkable things that these people have is they have no heart disease and no Alzheimer's disease. That tells you intuitively immediately, and this is what I discussed in the Peter Attia podcast, that the hypothesis for a drug like obicetrapib is that it would, if you basically lose CETP, that that would influence brain health as well as heart health. I'm going to take you right back to heart health and convince you that the early MACE reduction we saw in BROADWAY is totally real. We have very good explanation as to why it's actually more than you would expect on the basis of LDL alone. Let me take you back to this thing that we presented already one year ago. If you have a phase three lipid-lowering trial and you see an early benefit for MACE, you want to know whether it's a fluke or not. There are multiple indications that can help you make that decision. The first is that basically all the hazard ratios that you observe should be below one, not for a single outcome parameter, but for basically everything that you study. What's striking about these numbers, and BROADWAY is on the top and pooled BROADWAY and BROOKLYN on the bottom, is that the hazard ratio for all-cause mortality and CHD death, as well as the first four-point MACE, are all below one. That's already an indication because remember, a number of the PCSK9 inhibitor trials had somewhat more erratic data for their 12-month that then totally cleared up, by the way, when you saw their outcome trials. To see hazard ratios below one is a very, very good first indication that it's a real observation. The second is thdat if you add numbers, so if you start pooling the data as we did here for Broadway and Brooklyn, the hazard ratios are even becoming a little better. That is simply a question of power and numbers. That is also what you see because you can see that the hazard ratio in the pooled data set for all-cause mortality, CHD death, and four-point MACE are better in the pooled data than actually in the Broadway data. Now, this question about stroke is very important because if you go to Broadway and you look at death from CHD, non-fatal MI, sorry, you look at the composite endpoint, death from CHD, non-fatal MI, stroke, or coronary revascularization, clearly less in the obicetrapib arm. Death from CHD, less. Non-fatal MI, a little bit less. Then stroke, it's basically the same. Now, the coronary arteries are tiny. Any occlusion that happens in the coronary artery will lead to clinical symptoms very rapidly. Current medical practices, and in Europe, we're watching The Pit. We always like American TV series. The Pit is in Pittsburgh. The most important thing that these people have is the door-to-balloon time. I mean, these are doctors that are discussing door-to-balloon time as a quality parameter. You can clearly see that the current medical practice in the U.S., when you have chest pain, you're thrown into an ambulance, you're raced to a hospital, and there everybody does its utmost to get you to a balloon. You prevent the heart attacks that would have occurred 10 years ago. Ten years ago, this whole organization didn't exist. That's why total coronary revascularization is what is medical practice today. It's basically preventing the heart attacks in those small coronaries. So it's very, very relevant. Some people say, "Yeah, but your data are all basically influenced by coronary revascularization." Thank you very much. That's excellent because that's exactly what you want. The only thing that you can do now is stroke. And that has two reasons. Stroke arteries are much larger. In order to occlude those, it just takes longer. The second is stroke is not as organized as well as heart attacks. There are stroke units now where you're also rushed to a stroke unit. You do a CT scan. You see whether it's a bleed or an infarct. Then you get thrombolysis. Even there are people now starting to think about balloons and stents for those arteries. It's simply not as well organized yet. Stroke has always been an erratic endpoint in a short trial. Look at the Elli-Rokimab phase three data. There also was a disbalance, negative disbalance in stroke at 12 months. In fact, in the Odyssey outcomes trial, it had the best hazard ratio of any component. Do not worry too much about stroke in a short trial. There is a tiny disbalance, but that actually does not mean anything. You have to look at coronary revascularization first, non-fatal MI and CHD death. It is all moving in the same direction, which this slide basically is the second kind of evidence that it is real, that what you observe is a real effect. The third thing that you want to see is the shape of the Kaplan-Meier curve. Remember the whole discussion. I do not know whether because the mean age in this hall is about one-third my age. I was on the steering committee of the Jupiter trial, rosuvastatin, and it was stopped early. There was this accusation that it was stopped on a random high because the Kaplan-Meier kind of does this and this. If you stop it when it's this, you're on a random high. That was an endless discussion if people remember that they shouldn't have done it, et cetera, et cetera. You do not want a wavy Kaplan-Meier curve. What you want is a straight Kaplan-Meier curve. What you can see here, the green on the left-hand side is placebo, and the maroon is obicetrapib, is that the reason that these two Kaplan-Meier curves dissociate from one another is because the maroon one goes flatter. The reason for the separation of the curve is the fact that in the OB arm, there's less events happening. It is after day 200, which is exactly what you would expect. The first six months, when you give a lipid-lowering drug, nothing happens. Because what you do is you prevent LDL depositing itself in the plaque, and you wait for HDL to efflux cholesterol from the plaque. That does not happen in two days. That takes months. Then you stabilize the plaque. Once you have stabilized the plaque, there are less events, less heart attacks, less disruptions, et cetera, et cetera. That is exactly the time, two months. Then you see the curve separate. What you also want to see is that the separation at the end is more than at the beginning, which is very intuitive. Nevertheless, sometimes you see Kaplan-Meier go white and then come back again. That is not what you want to see. You want to see it going white and going whiter at the very end. A third or fourth possibility to do a reality check of your data is to do a landmark analysis. We've done that on the right-hand panel here. What you then do is you say, "Listen, all the events that happened before six months are useless because they happened while there was no effect yet on the arterial wall." I'm actually going to introduce a new zero, which is day 200 or six months. Then I'm going to look at the separation of the curve. You take out the events that happened in the first six months. You're only interested in the events in the last six months. Look at that hazard ratio, 0.66. It should be bigger than the overall hazard ratio in the trial because you've eliminated the useless events, not for that patient, of course, but for the analysis purposes. Those two things really strongly suggest that this is all very, very real. Now, then you come to the intellectually different part of this. Based on just LDL alone, we would have expected a 9% reduction in MACE. This is what Steve Nissen also said. You're going to have a 9% reduction in MACE. We observed 21.79 hazard ratio is a 21% reduction in MACE. How do we explain that 12% additional reduction? It's a very important intellectual exercise. I'll divide that up for you in three things. It is LDL particles and Lp(a) that I'll start with. Michael and I are strong believers in NMR assayed LDL particles, especially because you do not only look at LDL particles, but you look at small particles. Every bit of science points to the fact that these small particles, they can penetrate the arterial wall more easily than large particles. They are more easily oxidizable and therefore more harmful to the arterial wall. That is why these small particles are so important. This is some of the epidemiological evidence on the left and some of the biology on the right. I think that you have to look at the red curves on that graph. This is a situation, a dotted line. These people have high LDL particles and high LDL cholesterol, clearly very high risk. If you go down rapidly, that means you have more risk, more events. Even if you have low LDL but high LDL particles, you have also very high risk. Now, this situation where you have modestly elevated LDL but very much particles is a typical Western society situation. These are the people in our society that are overweight, insulin resistance, have higher triglycerides, low HDL, very often type 2 diabetics. Those are the people that you enroll in an ASCVD trial. In fact, if you do a trial where you enroll people for the marker of having ASCVD, 40% at least are going to be frank diabetics without even asking for it. You're going to get 40% diabetics, and 60% have metabolic syndrome. The vast majority of ASCVD patients in the U.S., especially, but also slowly in Europe. Everything that happens in America happens in Europe five years later. I mean, we're seeing those patients right now too. The particle patients, the patients with very high levels of particles, especially small particles, are basically in trials like Broadway and PREVAIL. That is important because then you have to ask yourself the question, "Okay, if that situation is what it is, what is our drug doing to that profile?" Here you can see again, these are very, very strong. This is a meta-analysis. Every dot to the right means that the particles have a predictive ability for heart disease over and above LDL cholesterol. I mean, these are kind of VA HIIT, Heart Protection Study, et cetera, et cetera. Eric, I mean, all the American big trials are on this graph. Just to give you a feel for the numbers, and now I have to kind of echo Michael because in Europe, we still do very little NMR particle work. Michael, when he has a patient and he orders an NMR profile of a patient with ASCVD, that patient is on high-intensity statins. That is the background therapy in 90% of Broadway, 90% of PREVAIL. These guys are on high-intensity statins. What does a statin do to particles? The statin preferentially lowers large particles. We've known that for a very, very long time. So these baseline LDL-P pooled Broadway-Brooklyn TANDEM are about 1,000. When you get a particle profile back from a patient, you get a number that's about 1,000, 1,000 nanomoles per liter. Of that, in that high-intensity statin-treated patient, small particles are 70%. Normally, they should be a minority. In these people, they are actually the majority, 70%. Whether you go to Broadway, Brooklyn, or TANDEM, actually in TANDEM, they were like 80%. Tandem is an all-American trial, telling you that in America, the small particle problem is even larger than in our international trials with contributions from Western and Eastern Europe and China and Japan. The next question then is, "Obicetrapib, what does it do to total particles?" It's about 40% pooled, which is 36% in Broadway, 52% in Brooklyn, and 60% in Tandem. That's very reminiscent of the LDL cholesterol lowering we had in those trials. We reduce total particles by about the same number as we reduce LDL cholesterol. Look at the small particles in the bottom. It's like wiped out. This is something that we honestly did not expect before we saw the data. Both in Broadway and in Brooklyn and in Tandem, placebo-controlled, basically a full reduction of small particles. You can go back to the biology literature and understand how these particles are formed. You understand that CETP is a key biomarker for the genesis of small particles. If you knock it out, by definition, you're not going to be able to produce them anymore. There is a very, very large reduction of small particles. We hypothesize that this reduction is helping the MACE reduction that we observed in Broadway. The changes in these particles associated with risk are, again, abundant. I'm not going to bore you here with the details. This is totally new. What we've done with Michael Zarek—Michael Zarek is our hope and trust. He's the professor of biostatistics at the University of Colorado. He did also all of the alirocumab work. He's very savvy in all of this. What you see here is the one-year cumulative incidence of MACE in BROADWAY on the left-hand side in the placebo arm across different baseline particle numbers. You can see clearly that in the placebo arm, if you have more particles, your risk goes up. That's very intuitive. That has been shown before in all those other epi studies that I showed you. The graph on the right-hand side is totally new. What you see there is that the MACE treatment hazard ratio goes down below one the more particles you have at baseline. Since the more particles, 70% of those more particles are small particles, here you can see very clearly that when you reduce these small particles by 100%, which is the major proportion of these particles, you're being paid back by reduction in MACE. This is the first data to strongly suggest that our small particle reduction in BROADWAY contributed to the MACE effect. The next question then becomes, how can we estimate that? The methods of estimating are actually on the left-hand side. There are three. Again, I want to keep this a little bit helicopter view. You can read this and agree with us, is that it comes down to about a 6% additional MACE reduction. LDL alone, as we said, 9% MACE reduction expected. Small particle reduction, 100% of the 70% of all the particles will approximately reduce MACE additionally by around 6%. Now we have explained 15% of the 21% in our calculations with our statistical geniuses, I would say. The next issue, and I'll just let this sink in for one second, is Lp(a). Lp(a) is even more intellectually challenging here than the particles. I want to make a few points. We have to stop thinking in milligram per deciliter. The new metric for Lp(a) is nanomole per liter. It is actually very helpful because in the general population and also in ASCVD patients, about half of all of us have an irrelevant Lp(a) level of less than 50 nanomole per liter. Realize that all this incredible attention for Lp(a) does not apply to half of us because we have such a low Lp(a) that it is clearly clinically not relevant. No one on the planet thinks of addressing a therapy to these people. You enter the risk zone at about 50. That is where the risk starts. If you go higher, higher, higher, higher, you enter the area where the siRNAs and the ASOs against Lp(a) started enrolling their trials, which is for Horizon around 150. The Amgen trial, I always forget the name, actually at 175. Sorry, that's the Lilly trial, 175. The Amgen trial around 200. You can see that willingly and understandably, these companies that wanted to show an effect of their drug on Lp(a) went for the highest Lp(a), above 150, above 175, above 200. If you look on the graph to the left, that is about 10% of the overall population or 20% of those with elevated Lp(a). Now, if the RNAi address 20%-25% of the elevated Lp(a), there is 75% of elevated Lp(a) that is not addressed by any ASO or any siRNA. That is always, of course, the situation in the beginning where you start, remember, lovastatin, first patient population, genetic high cholesterol, heterozygous FH. In the late 1980s, that is where you go first. You go to the upper end of the distribution and show that it works. You gradually come down. That nevertheless leaves the maroon area there between 50 and 150, 40% of the overall population or about 75% of everyone with an elevated Lp(a). The patients, the individual patients with the worst risk are in that upper distribution. They desperately need drugs. I really pray that the RNAi work because these people are in dire need of that. The population attributable risk is not driven by those 10% up there. That is driven by the 40% between 50 and 150 nanomole per liter. It's very interesting to realize that the risk starts at about 50. You can see these curves. By follow-up years, they go up. The blue curve is actually the first to the 50th percentile. You go up, and you can see that once you are in that very high region, it doesn't make much difference whether you have 200, 300, 400, or 500. The biggest bang is once you're over 150. It doesn't give much more information than if you're 250 or 350 or 450. Again, the large area below the blue curve tells you that the population attributable risk is between 50 and 150. I'm going to skip this one. Where does obicetrapib have its biggest bang for your buck? Exactly in that area. Look at the boxes. If you look in BROADWAY, in patients with a baseline Lp(a) between 50 and 150, in BROADWAY, it was 43%. In BROOKLYN, 52%. And in TANDEM, 52%. If you do a pooled analysis, it comes down to a 45% reduction of the Lp(a) between 50 and 150. As you can see, if you go to the higher end of the distribution, the efficacy of obicetrapib wanes off. Exactly the same thing is observed with the PCSK9s. It is very intuitive as to why that happens because people with very high Lp(a)s have small isoforms that are mostly genetic and are driven by overproduction of Lp(a) particles in the liver. In order to kill that, you need to kill their RNA. And you need an RNAi. These data show you that the RNAi are going to be massively beneficial for lowering, whether they're also massively beneficial for MACE reduction. I do hope and pray, but we still do not know. In that middle area, actually, our drug, 45%. What's interesting is that that leads to an absolute change of about 40 nmol/L. With that absolute change, you can do your math on the MACE reduction. The percentual reduction, exactly as with LDL, does not tell you much about MACE reduction. You need to know the baseline. You need to know the percentual reduction. You calculate the absolute reduction. With that absolute reduction, you go back to the Mendelian randomization and the epidemiology. You do an estimate. Remember, all of this worked pretty well for LDL. We have no bloody idea whether this also works for Lp(a). This is still, at this time, it is conjecture. I'm going to skip over this too. When we now do new data, a mediation analysis for Lp(a) in Broadway, it comes out that 26% of our MACE reduction that we observed, so this is 26% of the 21% we observed, is conferred by our Lp(a) lowering. Now, a quarter of 21 is about 5% to 6%. We can now, on top of the LDL, say with pretty good certainty that the Lp(a) reduction we observed in Broadway has actually contributed about 5% to the 21% that we observed. The methods of estimating that MACE reduction, again, are on the left-hand side. We have two. They both tell us exactly the same. I'll leave you with those slides and to do the math here. I think that, and I'm not going to repeat Michael, that would be extremely boring. It is becoming incredibly clear that the hypothesis I had in the podcast with Peter Attia and the notion that Michael and I had when we started the company and started developing obicetrapib, we had a lot of kind of pieces of information at that time that we knew from old CETP inhibitors. We knew from biology. We knew from the Japanese patients with no CETP at all. It is all coming together. I think that that's the main message of this rainbow umbrella. The HDL part on the left-hand side is very likely linked to the Alzheimer effect we observed and to the diabetes. The ApoE4 is brain health. The small LDL particles is MACE. All the ApoE and small dense LDL, MACE, Lp(a) MACE. Then we still have the new onset diabetes that was suggested by other trials. We had not seen it yet, of course. We can now show you and show you with a little pride, I have to say, because a lot of thinking, and especially Matt and Michael Zarek, there was a lot of thinking going into this bar on the right-hand side. LDL alone, 9%. LDL particles, an additional 6%. Lp(a) an additional 5%. There is this little 1% at the top, of course. That is very likely simply random variation around a mean or a median. We have a very good handle as to why this drug conferred a MACE reduction of 21% only after 12 months. The reason for that is that this drug does not only lower LDL cholesterol. It is LDL cholesterol plus. I've said what all the pluses are. I'm not going to repeat myself. If you don't believe in any of this, and you say, yeah, nice hypothesis, and Kastelein is ranting, and just let's move to the next meeting, just look at LDL alone. What would we need in PREVAIL for a 20% MACE reduction if we ignore everything we've done and seen and just focus on LDL cholesterol? That's about a 33% LDL reduction. What did we see in BROADWAY at day 84, placebo-controlled, lousy imputation and the whole works, 33%. The LDL effect we had in BROADWAY is enough to confer a 20% MACE reduction in PREVAIL. I think that if you ignore all the rest, at least this is a message that I think everyone on this planet would agree to. I'd like to finish with the diabetes stuff. I think I've done a lot of lecturing in the Far East, in Japan, in Southeast Asia, and especially in China. I've been to China many, many times. What is the worst fear of a Chinese patient? It's getting type 2 diabetes from a statin. That's why in China, in PREVAIL, we could not bring any patient to a dose of a statin like higher than 10 milligrams. They simply don't take it because they don't want to get diabetes. The idea that you have a drug as an ideal companion to statin therapy in those 1.2 billion people is, of course, a very attractive drug, both for health as well as commercially, of course. For Michael and me, it was very important to show that this drug indeed can confer, in a longer-term trial than BROADWAY, of course, confer a diabetes benefit. Why did we think this? There is a lot of evidence that raising HDL has antidiabetogenic effects. HDL itself can influence the beta cell in the pancreas by effluxing cholesterol. It drives glucose uptake in muscle. It instigates through sphingosine-1-phosphate insulin production in the beta cell. There is endless preclinical work and biology and epidemiology. Raising HDL or high HDL is very good for type 2 diabetes. Here you again see it. I am not going to—I do not like reading from slides. Believe me, this raising HDL is very, very good for type 2 diabetes. When The Lancet put out this report about two months ago, they basically now did a meta-analysis of any imaginable trial with a statin, and they showed that high-intensity statin—remember, that is what we used in Broadway and in PREVAIL, meaning 20 or 40 of Crestor or 40 or 80 of Lipitor. That's high-intensity statins. Look on the right-hand side in the blue box, hazard ratio 1.36. That is a 36% increase of new onset diabetes on the highest dose of a statin. You can certainly understand why the Chinese patients and also on the Indian subcontinent are not so very fond of going to a high-intensity statin dose. These are data that I think we just presented at NLA. We have to realize that we have to be very modest. Broadway was only 12 months. In order to see changes in glycosylated hemoglobin or new onset diabetes, was a bit optimistic, I have to say. To our, I would say, enjoyment, on the left-hand side, in the left-hand panel, this is glycosylated hemoglobin at day 365. OB is maroon and placebo is green. That difference, in fact, achieves statistical significance. Now it is clear that CETP inhibition protects against new onset diabetes by lowering glycosylated hemoglobin. We did not know this before. It could have been any mechanism, basically. That is the mechanism. There, and of course, at 12 months, it is still a tiny difference. If you look at the other CETP inhibitor trials that were three years, four years, or REVEAL six and a half years, the differences were much larger, of course, because it takes time. It takes time to kind of move that tanker around. When you do and you look at all the other CETP inhibitor trials at new onset diabetes and the top ILLUMINATE, dal-OUTCOMES, ACCELERATE, REVEAL, and then BROOKLYN and BROADWAY, then you go to the diamond in the bottom, and then you can see that the overall protection is about 17% if you do a meta-analysis. There is 17% less type 2 diabetes in the treatment arm than in the placebo. In fact, in Brooklyn and Broadway combined, we saw a 23% less new onset diabetes in the OB arm compared to placebo. That is almost a quarter. That is one in four patients. The translation of that is that in a trial where you put patients on high-intensity statins and you expect a 36% increase in new onset diabetes, you put OB on top, that 36% increase disappears and is changed into a 23% protection. Imagine that that actually is a very potent effect. These data are immensely welcomed in Asia. Of course, also here, but in Asia especially, I would say. You have to realize when you discuss these changes that they are on top of something that negatively influences that. Your drug first had to get rid of the increase of 36% and then actually on top of that, turn the type 2 diabetes around. With that in mind, we're going to do, and I think this is new, huh, Michael? This is new. We're going to do a trial in type 2 diabetic patients and patients with metabolic syndrome. We call it Rubens. Has anyone ever seen a painting of Rubens? What do the women look like? Very voluptuous. That's why we actually chose this name, Rubens. It's going to be quite large for a phase 3 trial, twice 100 people. What we want to see here, because we've seen in Broadway that our drug not only prevents new onset type 2 diabetes, but actually has by far the best LDL lowering and small particle reductions in the type 2 diabetes. This is going to be for us an important additional trial. My throat is dry. Fortunately, BJ is next. Thank you very much. I appreciate the opportunity to engage with today's panel. I hate following John because he always does such an excellent job of communicating. He did a wonderful job, essentially of outlining what is the benefit of obicetrapib and OB-EZ and what that looks like from a clinical profile standpoint. Hopefully, he answered those questions around the why. What I'm focused on today is to actually talk about the so what from a commercial standpoint. What's the implications of that differentiation? How important is it? What does it mean in the marketplace today? What we'll do is we'll walk through, if you will, kind of four different areas, if you will. Again, I believe that at the end of this discussion, we will all have a dialogue, and you all will hopefully be in the space that I am, where you're just excited and can't believe that we're on the edge of what is a transformational launch in the lipid-lowering space. Nothing has been introduced into the space like OB. We'll talk about that. First, we're going to spend a little time on market opportunity, just as a reminder of how large the market is and what we've seen in terms of overall growth and acceleration in that space. Number two, we're going to talk about this differentiated product. We rehearsed what John said, but we'll talk about why that's relevant as we think about patient segments within LDL lowering. We're then going to talk about how do doctors actually perceive that? What does that look like? What's the implication? What will that mean for prescribing behavior? Lastly, we'll talk about commercial launch and what we think our unique opportunity is in this space and how we also believe that we're uniquely positioned to do this extremely well. Let's start with that market opportunity and kind of go back and rehearse what we talked about before. Overall, there are strong tailwinds in this marketplace that we actually see lipid-lowering space far more conducive to commercial success. There are a series of reasons around that. One of which is, like an observation, we've certainly seen the LLT market continue to grow for the last five years or so. It is already a very large opportunity, so large that even small amounts of penetration actually mean a lot in terms of what is the financial success on the end of that. As it relates to non-statin growth, that is even growing more rapidly. We see that kind of extending forward, which is very good news for us, but better news for patients. There is a shift towards what is kind of more aggressive treatment in terms of using alternatives in addition to statins. There has been a shift in terms of guidelines. You all are aware that in the early 2010s or so, there was this move away from goals. That has been reintroduced and in some sense now even at lower thresholds. We will walk through that as well. From an access standpoint, if we look at just access to PCSK9s, that has actually been broadened. It's a good thing because that access has been increasing. There's been a breadth of utilization. Payers are actually willing to cover these products. Lastly, we'll focus, if you will, on what is the market leader. That's Repatha, where we'll talk about what has been kind of their growth over time, what that looks like in year 10, essentially of launch, and basically shows that they had almost 50% growth in terms of volume over the last 12 months or so. Again, it's another reason to believe that there is opportunity for commercial success in this space. If we look and basically start on the left-hand side, just as a reminder, 72 million folks already diagnosed with hypercholesterolemia. 10 million of those folks are actually not on a product. Another 30 million or so are actually not at goal, even though they're on statins or some other lipid-lowering treatment. They're still not at goal. Forty million folks there are kind of in that sweet spot, if you will. The next category basically looks at just the overall LLT marketplace, which is predominantly driven by statins, of course. We see what is about 4% growth or so. That's acceleration over prior years. That 4% growth, again, is a reminder of how large this marketplace is. It basically is an equivalent around 9 million or so additional TRXs that are in the market. We expect that to continue to grow and accelerate over time. If you look at the next category and just talk about non-statins, which is primarily driven by ezetimibe, which you can see, again, very strong high double digits north of 20% in terms of growth. Of course, on the right-hand side, when we look at branded TRXs, we actually see that driving even north of 30% or so. Importantly, I'd say that's very strong growth. That's a positive sign. We see an acceleration year over year. We expect that to continue. There we go. All right. If we look at guidelines specifically, and again, there's been kind of a move towards more aggressive intervention. In 2018 is where we actually saw kind of that first anchor where we went back to goal setting. That was established at an LDL-C threshold of 70 milligrams per deciliter for non-statin therapy to be added. In 2022, we actually saw that reduced to 55 milligrams per deciliter. Earlier this year, we actually saw that same threshold, but now for hospitalized patients with ACS. Again, there is kind of this breadth of push for more aggressive intervention, which is certainly necessary to address what essentially is this cardiovascular death growth and acceleration, unfortunately, in that death as well. When we look at U.S. regulators, what has been done there? I'd say that there has been a recognition or so of that unmet need in LDL lowering. Essentially, they have taken steps to address that. If you look just at broad labeling within kind of this market, we can see that language in those labels has actually evolved over time. With that evolution, we've actually seen kind of reduced access restrictions. Payers now are covering more. That allows for what is expanded use of treatments actually beyond statins. That has helped to drive what is this market dynamic, if you will. We use and look at basically a couple of examples. That's Leqvio, as well as Nexlizet and Nexletol. Once, again, that they had evidence of outcomes, those labels did change. We kind of expect that to continue. There's a push. The difference, the important difference, again, is that the previous labels had utilization of these non-statins in HeFH or clinical ASCVD. That expansion, if you will, is for adults with primary hyperlipidemia. There are also a number of other critical factors that contribute to what is this kind of broader utilization, specifically as it relates to branded market dynamics. This is not all-inclusive, but these are the primary areas. People talk about this all the time. Number one is when we look at access, there have clearly been changes in terms of pay and reimbursement. We have seen significant change in what has been an increase in overall approval rates. What we are using here is evidence primarily anchored into what is the brand, the market leader in Repatha, which you certainly see a significant difference from past years to recent years in regards to approval rates. It is much easier to write and prescribe and then actually have patients go get access now to Repatha. The same is true when you look at promotion overall. There's been an increase and an increased investment in that promotion. That's done from a 360 perspective where you see that certainly in DTC. I would say that's true in both what is branded and unbranded DTC. Also, when you look at direct promotion as well, kind of increasing by more than twice the number of people that are in the marketplace, whether they be reps or other customer-facing roles. That's increased what has been that promotion. It's driving essentially what we see on the right-hand side here, which is like a breadth of prescribing. There's been increased depth of prescribing. Importantly, we've also seen the extension beyond what is just specialty into primary care. That sits like the vast majority of this population. Repatha, we see they've even recently talked about when in terms of PCP writer base has grown by more than 30%, which adds about 24,000 or so new PCPs who are writing over the last 12 months. That leads to essentially what we see here. You all are well aware of what has been kind of this accelerated growth of Repatha. They had a tough start right out of the gate, a lot of reasons, pricing, tremendous access issues. Payers basically put the clamps on. That has actually shifted over time. It took them five years to get to their first million prescriptions. It took them two years to get that second million prescriptions. In the last two years, they've actually doubled that. That has actually led to what recently reported out is just north of $2 billion in terms of worldwide revenue. Half of that is in the U.S. itself. When we look at the PCSK9 class broadly, looking at about $4 billion worldwide. That, again, I would suggest is very, very good news, more importantly for patients, but certainly good news for us as well as we see what is a pathway to what is a very, very large market that is actually growing. That is looking back and looking currently at what is happening in the marketplace. Truly, we also see we are not the only ones who see this data clearly, right? We look at Merck and AZ, who obviously have products in the pipeline in the space. They also see what essentially is a bullish outlook for the size of the market and the opportunity to really address what is this tremendous unmet need. When you look on the left here, Merck has actually communicated in this particular presentation, they talked about their entire CV pipeline. Looking at the entire portfolio, they talked about greater than $10 billion in peak revenue. Something recently that came out, they talked about $15 billion in total revenue, of which MK0616 is a portion of that opportunity. When we look at AZ, just recently, they talked even more specifically about just their oral PCSK9 being a $5 billion-plus asset. I would suggest, again, that there is a place for these products in the marketplace. There is tremendous unmet need. They will certainly do well. I hope at the end of this discussion, you will see that we will just do much better. Let me talk about that as it relates to kind of setting the stage for what is this transformational launch. We'll build upon what John had talked about and how it relates to the incredible opportunity we have for what is this differentiated positioning of LDL Plus in this space. Once again, we'll just start with kind of anchoring into we're talking about OV as well as OV plus ezetimibe, which essentially is our franchise. Tremendous evidence supporting all of this, as we all know. Very strong phase two programs. Very proud of what is successful phase three programs. As John and Michael have talked about, we now are anxious to continue to push through with the excellent job that Doug and his clinical team have done around PREVAIL, Rembrandt, Vincent, and now introducing the Rubens study as well. In the current space, essentially, right, the marketplace is dealing with LDL and how that influences what is MACE reductions. That is the space that we are currently working in. As you've heard, basically, we're talking about the future of hyperlipidemia and treatment. That goes beyond LDL-C. We are looking again towards essentially a future in which clinicians will suggest no longer is LDL-C enough. We actually want to be able to treat across multiple areas of risk, addressing what is LDL-C, of course, but doing much, much more. That is a unique opportunity that this particular drug can fill in the marketplace. Again, OV is observed to impact multiple factors that are associated with MACE as outlined for us. Importantly, I want us to think about the patient segments, right, subpopulations that are specifically thinking about this and how doctors will think about it as they write going forward. For instance, let's start with LDL-P and particle concentration. Approximately 43 million patients with hyperlipidemia actually have these elevated levels of LDL-P. John mentioned 1,000 or so, but we just looked at 1,300. Prevalence is actually higher in type 2 diabetes in these folks. The presence of just particles is a significant independent risk factor for CHD. If you think about that 43 million patients or so of the 72 million, and then you ask, "Okay, now you're a clinician and you're sitting and you're making a decision and you recognize that you need to reduce LDL in that particular patient because now statins is not enough." You go to your sample closet, what are you going to reach for? The ask is, "If I have a patient that actually needs to reduce LDL, I certainly have an opportunity with OV and OV-EZ to have best-in-class efficacy in that space. If they also happen to have elevated particles, I'm going to reach for OV every time because there's a unique benefit in that regard." The same is true when you talk about Lp(a) in the U.S., close to 75 million patients or so have elevated Lp(a) north of 100. There is an estimation that about 14 million of those folks also have hypercholesterolemia. They are in that space again where you are addressing the needs of a particular patient with LDL. They need to reduce that. If they have elevated Lp(a), what are you going to reach for? You are going to reach for OV to address that unique need that only this product can address. Similarly, when we look at new-onset diabetes, and these numbers are massive, it is not a surprise to anybody. About 28 million or so of these folks actually with hyperlipidemia have concomitant diabetes. In addition to that, about 27 million of those folks are in the space where they are pre-diabetics. We are talking about 55 million people of the 72, essentially, right, that fall in these categories. Once again, if you have to reduce LDL in a patient that actually is in either of these categories, what are you going to reach for first? It's OB, OB ezetimibe, because it addresses uniquely what is that incremental benefit. Lastly, we take a look at what is, or what are, I should say, ApoE4 carriers with the new data that we're looking at. There's more work that needs to be done in this space. In a similar sense, if we think about and recognize ApoE4 is the strongest genetic factor for late-onset Alzheimer's, there's approximately 20 million patients or so that actually have hyperlipidemia who fall in this category. Right? Once again, and Michael talked about essentially what would be kind of the activation, the motivation for patients and clinicians, frankly, to try to address what is this risk associated with people who need to reduce their LDL. Once again, where are you going to reach? You're going to reach for OV, OV-EZ. To be clear, we're not talking these are not additive, right, where you look at 43 million in this area, 14 million, and add that. There's certainly overlap there. There's concomitant disease and the like. The message is clear is that it's a significant portion of what are the 72 million folks out there that are diagnosed with hyperlipidemia. When you look essentially at what is currently in market and that which is in the pipeline coming to market, again, to be very clear, there is a place for all these medications. This is a massive, massive market. There is tremendous unmet need. We need clinicians need and patients need options. It is good. There is a place for each of these. What I would suggest to you, however, is that no other asset provides what is the comprehensive observed benefits of OV and OV-EZ to address cardiometabolic risk, right? That is a very unique positioning that only we can provide. That is for those products that are currently in the marketplace as well as anything coming, right? With OV and OV-EZ, we certainly have an LDL plus, if you will, clinical profile that has been clearly identified and communicated by John. Safety and tolerability, very similar to placebo. It is simple. It is oral. There is still a preference for oral versus injectable once daily and low dose. It is really an optimal profile for clinicians to write and for patients. Now let's talk about how do actually physicians perceive that? What does that mean in terms of what they perceive their writing behavior to be? I'll introduce you essentially to what is some data that we've been able to achieve from a demand study. It's primary research where we've actually gone and spoken to over 1,000 doctors over the course of years to basically outline what is our TPP to get their feedback, both qual and quant. I can tell you that recently, as recently as March, we did our last demand study. That basically was able to incorporate all of our phase three data. We looked at that and their perception of the market, what was available in the market currently, what it is, the unique profile that OV, OV-EZ brought. We looked at that basically versus MK0616. We used their phase two data as a comparator in that space. I'd suggest to you again, if you take a look at this and the one question that we talked about is how likely are you to prescribe OV, OV-EZ in the first six months after it becomes available? The good news, three out of four HCPs basically indicate a propensity to write this within the first six months of availability. The next couple of slides, we'll go into a little bit more detail when you look at broad attributes and how they looked at these attributes. A bit of a busy slide. Let me kind of orient you to this if I can. Along the x-axis, essentially you see different attributes that clinicians had a chance to review. It goes from the left to the right basically in terms of relative value and importance, right, to those clinicians. You started with LDL-C reduction, most important, affordability is right along that side all the way down to what would be appropriate for all patients. The clear takeaway from this slide is that OV and OV-EZ perform statistically better than what will be the Merck oral PCSK9 on several of these key attributes. Let me just kind of poke out a couple here. I'd suggest that over time you guys take a look and go through this data. Whatever questions you have, please bring them forward. When you look at LDL-C reduction, when you look at our overall portfolio, OV-EZ is seen as on par with what will be the Merck oral PCSK9. Similarly, when you look at OB-EZ or what will be the franchise, it's seen as more affordable than MK0616, which is interesting because when you ask clinicians, like, neither of these products are actually on the market, there's no pricing, all of that. Their perception is that because of the issues PCSK9s have had over time, there's a bit of a negative halo there. We get kind of a bit of a break on that one. When you look in terms of dosing schedule, tremendous variation there in terms of the benefit of OB, OB-EZ versus what will be that PCSK9. Lastly, on the far right, we basically see, and this is very important for us as we think about not just will we win the market share dialogue, but actually will we be able to expand and broaden what is that broad use? This essentially suggests that OV and OV-EZ are seen as more appropriate for all patients versus what will be the Merck product. As we go to the next slide, it's a similar setup. It goes to what are the next set, if you will, of attributes, right, along the x-axis. I will say too, it's interesting because today these attributes do not rank very highly, relatively speaking. I'd suggest that as we go forward, because of the dynamic that John talked about, how differentiated our product will be, we think there will be a rejiggering or reshifting, right, where doctors will actually value mechanism more than they currently do. They will actually value what is HDL increase more than what they currently do. The other interesting thing on this slide is basically there is one area, like MOA is the only attribute across all of these attributes in which MK0616 scores higher than OB-EZ and OB-EZ. The rationale, of course, is when we got from the qualitative is that they're just familiar with PCSK9s and with that MOA. We will spend time tirelessly communicating over the next couple of years why it is that CETPs are unique, why they're different, and why in some sense it provides this broader halo or rainbow, right, of benefits that PCSK9s cannot do. Lastly, as I mentioned, HDL-C attribute is not considered as important as others, but clearly there's tremendous variation there. It's our job to make that more important over the course of time. What that leads to is essentially the following, right? It's the positioning of where does this fit in the overall patient journey in doctors' minds as they look to prescribe and with what we believe is this differentiated LDL plus profile, OV is positioned to become the first choice add-on therapy to statins, right? Why is that? Again, it's because we can address whatever the need is fundamentally to reduce LDL. In addition to that, if you happen to be someone who has a comorbid condition of increased risk of LDL peak, you're going to reach for OV. If you need LDL to be reduced and you're pre-diabetic, you're going to reach for OV. Similar with Lp(a) and potentially ApoE4 carriers as well. That's where OV will actually fit, right, into that prescribing continuum. When we think again about the size of the market and how we're seeing this broader utilization beyond statins, right, that's why we have such a big opportunity here in this space. I couldn't be more excited to be on this team and actually be ready to do this, which is launch this product. Before I tell you just how big we think this opportunity is, I do want to mention for a moment that the question is out there, of course, some of you asked this morning, is that, okay, great product, obviously, tremendous opportunity from a differentiation standpoint, but how is this little company going to do that? Like, can we really go up against what are the big BMS in the marketplace and not say, not only can we, but we will and we'll be extremely successful? Not only just myself, but the team that we've been able to build here and bring and invite to be a part of NewAmsterdam's story. We've been very successful over the years, not just with Biohaven, but actually beyond that, multiple blockbuster launches. So we know what needs to be done, the manner by which it needs to be done, how we need to build and scale for appropriate capabilities, and how to do that in an efficient way. We're going to enter into a marketplace when we launch. It's going to be different than the way we launch today, but we're nimble and we'll be able to take full advantage of what is technology, omnichannel to make sure that we're effective and are able to efficiently engage with not only physicians, but also patients in a unique way. That is a benefit on top of this unbelievable product that we have. What does that mean? What it means is those demand studies we just talked to a moment ago essentially suggest that we will be the preferred add-on over not only Merck's oral PCSK9, but also AZ's as well. We know that's a few years out, but we actually included that in the information. Basically, this suggests that, as I said, MK0616 will do well. There's a place for this in the marketplace. It will do well because of what is this tremendous unmet need. We see that response from clinicians essentially says, at least with the profile that we believe is out there from AZ, they'll do a bit better. Very clearly, it basically shows that there will be 70% more demand for the OV franchise than what will be the more eminent competitor, which is Merck, right? This is clear not only in the U.S. It's not just a U.S. phenomenon, if you will, but we did that and we've done this research across the globe. These are just two examples, but we look at Japan and we look at China as well. We see that basically this preference transcends diverse cultures, treatment preferences, healthcare systems, and the like. This is real. I think importantly, understanding that and clinicians actually perceiving this as a real important differentiator where they get incremental and added benefits for the patients, they see the value and it's reflected here. What does this mean as it relates to our overall blockbuster potential? I'd say if we rehearse again, massive marketplace, significant unmet need, which is also recognized by the competitors, right, in the pipeline, they both essentially say it's going to be multi-billion dollar opportunity for them. Our unique differentiated profile, not just the fact that it's different, but the meaningfulness of it, how relevant that is, and what doctors are actually suggesting to us, how that's going to impact their prescribing differentially, that's the opportunity, which basically translates into what is greater than $8 billion worldwide potential. Again, we anchored into what we saw both Merck and AstraZeneca talk about. As I said to you, based upon the profile of this product, we expect to do even better. There's a big opportunity ahead of us. We'll take full advantage of that. I know people generally, you all ask for all the right reasons, like what about access? Like, do we see a barrier there? The answer is, at least from the feedback we received, we've done a lot of work in this space. We've had payer advisory boards, as you might imagine, but more importantly, we've been able to engage very specifically with all the PBMs and specifically with payers. We had over 40 of these PI conversations with them in which we've shared our data. Essentially, the feedback has been very strong. The theme is essentially here where they basically, payers generally feel that they've been able to control the LLT space. They're not really scared of just how big this is going to be. They said that we should expect broad coverage similar to PCSK9s and bempedoic acid. Evidence does suggest, and we see this right now, is that there's a reduction in what are prior authorizations. Much more simple than they actually have before. OB is anticipated to be established as what is a very new class, which actually benefits us in negotiations and dialogue with payers. They do value what is the incremental benefit of this differentiated data. They will appropriately engage and work with us to get on formulary, to add choice, right, to that. Lastly, importantly, payer feedback consistently reinforces we should expect broad access based upon what is the TPP that we share. Again, what others have unfortunately run into historically in this space, we do not see that because of evidence currently in the marketplace of the change in the more open or relaxed environment, if you will, around access and the feedback that we specifically gotten from engagement with these decision makers. Okay. Overall, as we wrap this thing up, the stage is definitely set for OB to be a transformational launch. We believe that because everything that we have talked about thus far, like things are lining up extremely well for us. The market opportunity continues to expand. It is growing, other folks, and it is a far more receptive marketplace than it has been historically. There is no doubt that our product is differentiated. I think that is very, very clear, right? The question is, is it relevant, right? And the answer certainly is yes, based upon clinicians, over a thousand of whom told us this over time with very strong and comprehensive primary care research, or primary research, I should say. HCP strongly, strongly favor the OB franchise as we have seen. Listen, from a commercial launch standpoint, we absolutely are focused to revolutionize what is the LLT marketplace with an LDL plus profile that no one else on market or coming to market will be able to deliver against. What we think that will deliver, if you look on the right-hand side, this is illustrative purposes only, of course, but we expect, we see what is nice current branded growth, and we expect to kind of enter into what is that more receptive marketplace. We will do at least that well. What we expect to do is the following. Because of what is enhanced demand, because of our unique profile, we expect to jump the line, if you will. That is the overall opportunity that we see that will lead to the big number that I shared with you earlier. Let me close out on the following, which is the reason why we're all in this game in the first place. Please meet Kerry B. She's actually a real patient who actually is in the Chicago land area. The reason why we're so focused on this and so focused on making sure that we can make a substantive impact in this space is that CV death has been growing and not just growing, but accelerating. We've got to stop it. If you think about Kerry and all the other patients, look at what she says, "Having heart disease weighs on me every day. I feel like I am walking a time bomb, waiting for it to be my turn to have a heart attack or stroke. I've worked so hard to take care of myself, but I still have markers that put me at risk. I'm so grateful to have a cardiologist helping me to take control, but I'm always thinking, is it enough? Is it enough? There are millions, as we know, of patients just like Kerry. If you look actually at kind of her medical history, Kerry absolutely has high LDL-C. She needs a product to actually help address that very specifically, but she also has elevated Lp(a). Now that's Kerry. Suzie is someone who actually needs LDL reduced, but she actually has increased particles. We have others, of course, who will have those other patient segments that we talked about. Once again, doctors are going to think, how can I address what's necessary in the fundamental lowering of LDL-C? We do that as well as anyone, and we're safe and tolerable. In addition to that, where there's increased risk in any of these areas, they will reach for OB before they reach for anything else. Let me stop. I will pass the baton back over to Michael. Thank you for your time. Thank you all again for attending. We're going to have a panel discussion. Before we get to that, just a few concluding remarks, and then we'll open up, of course, to what you, I'm sure, a lot of burning questions we'll hope to get to in that discussion. Like I said, we could not be happier to be where we are today. Again, a year ago, we were at an exciting point prior to our phase three data. We can honestly say that obicetrapib delivered on such an exceptional product for our patients. You think about the company, I've got a magnificent drug, I've got a magnificent team. We have the clinical expertise. We've always performed exactly, if not ahead of schedule for all our clinical development programs. We have this, as BJ and John and I have been saying, a product that is so differentiated from any other LDL lowering therapy or any other cardiovascular therapy for that matter. I just want to highlight again, the patient journey is all about what motivates that patient to start taking a therapy. Today, again, speaking as a clinician, it's always a challenge. We're recommending a new therapy. There's always pushback. Is it safe? Is it effective? Will I have side effects? We have obicetrapib, has that exceptionally good tolerability and based on our phase three data safety profile. Then you come back to the overall differentiated features, the Lp(a), the ApoE4, the diabetes risk, all those things really make the patient much more highly motivated to take something that's going to address his other life-threatening conditions. The unmet need, I don't know if people realize what these new guidelines mean for the marketplace. We're going back to the 1990s now as far as new people that need to be treated or new therapy to be added to achieve the goals. That's when statins exploded because we had a therapy that could get people below 100 LDL. Now the LDL is 55. That's basically we're back to where we were in the 1990s when it comes to the unmet need for achieving LDL targets. We have experienced leadership across the board on this team. You'll see the capabilities. I'm blessed with a team that has performed magnificently as well as the drug has performed. You're hearing it from the medical community, the KOL support. We wanted to have KOLs today, but we ran out of time to have this discussion broadly. We have so much support from our KOL community throughout the world. Our CMC team is the unsung hero behind the scenes. They have done a fantastic job developing this drug and developing a robust supply chain that makes our life easy when it comes to delivering this drug in the future for both trials and ultimately commercially. As you saw from BJ, we have someone in his team who have been there, done it before with great success. I know they feel even more excited about this drug than any other drug they've had the ability to launch in the past. We really feel we have the right team to bring this drug to patients and a very strong launch to follow in the years to come. We are also blessed with a strong balance sheet, thanks to our finance team. We are able to, and our partners in this room, we have the balance sheet we need to bring this drug all the way through to the launch in the near future. Thank you all very much for coming, and we look forward to your questions. I will have BJ and John and Ian step up to the podium here and sit in the chairs. Questions, yes. Tyler, start with you. Do you want to have the microphone? Okay. Michael next, John. Oh, sorry. Tyler, great. Thanks very much for the excellent presentations. Tyler Van Buren, TD Cowen. Just wanted to follow up on the selected four-point MACE endpoint for PREVAIL. Could you elaborate on the selection of the four-point MACE? Was it the analysis showing that stroke separates after a year that gave you confidence to use the four-point MACE endpoint, or did you look at the data and kind of separate the ischemic stroke data versus the other types of stroke that are less affected by LDL, and therefore it did not have a meaningful negative impact on the 12-month MACE data from BROOKLYN and BROADWAY that gave you confidence in selecting the four-point endpoint? Right. So yeah, we can go. You first. Okay, go for it. We did have total stroke in that Broadway analysis, but when we looked at hemorrhagic stroke, it made a difference of one or two. It was not a major effect. It was predominantly ischemic stroke. As John said, stroke is a little bit harder to adjudicate because you have embolic stroke, you have hemorrhagic stroke, and you have ischemic stroke. Embolic stroke gets kind of classified as ischemic stroke. An embolic stroke is typically atrial fibrillation and things like that. It is not something that is LDL mediated. When we did that, we did not see much difference as far as the Broadway data, but what was convincing for us were the two factors I brought up. One is that in all the other trials, we looked at every single trial. You can go through the list. The one that's probably the most stands out is PROSPER because that was a pure statin for stroke reduction. At one year, the curves are right on top of each other. There's no separation. Sparkle. A sparkle, I mean, sparkle. Sparkle trial. No separation in stroke. We then thought about the new FDA recommendation or guidance that we could allow the whole composite to be in the label. From a commercial perspective, having stroke in the label is an indication, especially with our Alzheimer's benefit and ischemic stroke and that element of dementia. Now with Alzheimer's dementia, we thought it was very important to include stroke. We do believe that stroke will ultimately be positive going long enough. That is what all the data shows. For us, and I think, of course, there are other factors you have to consider, like the European regulatory authorities. They really want stroke in the three-point MACE. It really ultimately became, I think, a pretty consensus decision to keep ischemic fatal and non-fatal ischemic stroke as the endpoint, as one of the composite endpoints. We actually debated all four of them, of course. CV death includes death from heart failure, which is not modified by lipids. That choice was easily made. I think also that both TIMI as well as the Cleveland Clinic now have CHD death as their preferred term. Stroke was exactly like Michael said. You have REVASK. This is also Cleveland Clinic backed. We have people like Steve Nissen and Paul Ridker in our ed board. We discussed this with them also, that there is no difference anymore these days between all these different terms. You have hospitalizations for unstable angina, urgent revascularization, ischemia-driven revascularization, and then simply total coronary REVASK. In fact, Michael and I went with every case in Broadway that we called total REVASK was also ischemia-driven. It met the definition of ischemia-driven REVASK. Since a REVASK per se is so easy to adjudicate, if you put a stent in, I mean, every, I won't say the word, but everyone can actually understand that that's an adjudicated stent. That's a REVASK. All of those things combined made it actually quite easy at a certain point in time to say, okay, CHD death, fatal and non-fatal ischemic stroke, non-fatal MI, and all REVASK. I think it just makes sense. Yeah, we look at urgent and non-urgent REVASK, and the hazard ratios were identical. It's like 0.68 for both in BROADWAY. For us, it's actually, right now, it's a lot easier to adjudicate all the events because CHD death is basically a fatal MI. Then you have non-fatal MI, stroke, ischemic stroke, just have to rule out hemorrhagic stroke. All REVASK is easy to adjudicate. It becomes a lot more clear-cut what the endpoints are for PREVAIL. Stroke these days gets a CT scan. And then once you have the CT scan, you can make the distinction between a bleed and a stroke. I mean, so it's different than 10 years ago when in America, most REVASKs were wallet-driven instead of ischemia-driven. That's all over now. And so yeah, there's a new situation that really cries out for this composite four-point MACE. Yeah. Maybe one more thing I'd add to this is when we were having that discussion internally, the starting point was confidence, confidence in whether we selected the three-point or the four-point MACE. Ultimately, it was really to get the broadest possible label claim. Okay, that's very helpful. Maybe just a quick second question out of curiosity. The anecdotes regarding the Japanese patients and not wanting to go on high-dose statins or the Eastern population makes sense, right, given the diabetes risk. Obviously, improving diabetes with OB treatment is beneficial. What do you think is the likelihood that maybe patients in the real world will be able to lower their statin dose and further reduce their diabetes risk once they're on treatment with obicetrapib or OB-EZ? That'll definitely help. I think that I can say that Michael and I are both not great enthusiasts for driving patients to the highest statin dose. There are many reasons for it. Diabetes is one. I was very deeply involved, I see Adele there, in the early atorvastatin trials and in TNT and all these trials. It was very clear that 80 mg of atorvastatin had much more side effects than 10. Also, for liver AST and ALT elevations were 3% versus 0.8% or something for the 10. There is much to say. Also, there is this unfounded belief that when a doctor drives you to the highest dose of something, there is bound to happen something. It is this, no, you are getting the highest dose. It does not sound good. I think, Michael, you too. We are more proponents of that. No question, Tyler, that with obicetrapib on board, it's going to be people are going to cut the statin doses down. The patients always ask for a lower dose. Always. It's part of the new patient model today. Less drug, lower dose. So having obicetrapib on board certainly brings that opportunity to patients. Great presentation, by the way. My name is Dennis from Jefferies. I just have two questions. Back in December, six months ago, when you guys presented the Broadway top line, you guys made a comment that the MACE benefit that you saw at one year is typically 50% of the MACE benefit over the entire course of the trial. On the conference call, I asked you, hey, look, should we be expecting perhaps a 30-40% MACE benefit since you guys were so far above the curve? Essentially, you guys talked me off that ledge. I'm curious. Today, I'm going to ask you the same question with all this additional analysis on Lp(a) and small particle LDL. Do you have any kind of updated thoughts? Question number two is just around all-cause mortality. Can you comment on the blinded events if that's been generally on track? Thank you. I think the last question is easy. Yeah, I'll do the last one. You do the first one. Okay. Okay. You do the first one. I'll do the first one. Yeah, go ahead. Dennis, you should never ask the same thing twice. I know it's very attractive for us to speculate about MACE reductions in PREVAIL, but I think it's very, very dangerous. The only thing that we can with great certitude do is to explain to you why we saw more than we expected in BROADWAY. And these observations on LDL particles and Lp(a) are not just seen in our trials. I mean, they are seen in observational epidemiology. They're seen in Mendelian randomization. It's not as if we just magically, I mean, take something out of a hat. This is not a standalone observation. It is likely, I think, that what we can say at this point in time is that it is likely that the LDL particle reductions, especially the small particle reductions, as well as the Lp(a) lowering will help our MACE reduction in PREVAIL. I think that we can say that with great certitude. I'm not going to end up with a game where I now make a prediction of what we will see. We will definitely see, I think, anything above the 15% that the PCSK9 monoclonal showed. That is still for us the bar to be better than the PCSK9s, both Odyssey outcomes as well as Fourier. That is more than 15%. Now, you can do with all the data that we showed you today, you can do your own math, but I'm not going to do that for you. I mentioned we're right on track with PREVAIL. We've had eight DSMB meetings. Everyone has gone very well. I mean, we don't know exactly what they say, but the meetings are very quick. They move forward, no changes. We've had that happen so far. That gives us, again, optimism that everything's on track from a safety perspective. Now we're settling on this four-point MACE. We've done all the analysis of events. We're very much on timing then for this end of 2026 completion of the trial. That's based on this composite four-point MACE. We haven't disclosed exactly what number of events we're expecting because we're keeping that into our design paper we'll publish relatively soon. Once we finalize everything, we have to go and finalize the amendment with the FDA. Once we get that done, we will publish our design paper. That is where we are. We are right on track. We feel really good about the timing of everything for finishing PREVAIL at the end of 2026. We are extremely well powered for the primary outcome. Thanks. It's Leo from RBC. I had a question primarily, I guess, for BJ, but curious what the rest of the team thinks as well. One of the things I noticed in the survey that you ran is that the most important thing for physicians was actually LDL reduction even more than CV death or MACE. We know that the oral PCSK9s have pretty significant impacts on LDL reduction. I appreciate the differences are pretty subtle. We also ran a survey that sort of suggested the same thing that you guys saw. I guess I'm curious, is that like a perception you're going to have to overcome that outcomes is going to be more important than just the raw number of lipid lowering? Is that different in the community versus the academic setting? How are you going to sort of fight the perception that there might exist that oral PCSK9s are going to be more effective because maybe their lipid lowering number is just going to be higher? It's a very good question. I'd say the following is that the data suggests thus far that clinicians are just looking for something, frankly, in the neighborhood of what is that efficacy. Again, when we look at the franchise as a whole, OB and OB-EZ, we basically deliver again against what's 50% reduction in LDL, which is in the neighborhood. That's why we saw the reflection essentially that saw us as equivalent from an LDL-C lowering piece. I think what we don't want, we're not going to swim upstream, right, and try to convince everybody, no, forget that LDL piece. What we're suggesting is, no, no, no, LDL is very important. You need to address that, bless you. You need to address that. In addition to that, that's not enough anymore, right? We think, obviously, there's an education associated with this. There's a lot of communication that needs to be done. Thus far, even in what's early primary research, we see that that's not rocket science. People actually feel very confident about, wait a minute, I can, let me give you an example if I may. A couple of weeks ago, we were at an ad board. One of the clinicians, you remember this, Michael, one of the clinicians said that when they were coming into the ad board, they were excited about the data. They were like, you know, it's good. I see efficacy I was looking for, certainly safe and tolerable. That's fine. They were kind of struggling to think, okay, it'll be part of my repertoire, but why would I choose this specifically? We started to show the benefit and the differentiation of what we can bring and the incremental benefit that no others could. This particular clinician actually said, wait a minute. When I have somebody that I need to reduce their LDL and they happen to have elevated Lp(a), he said, that's a no-brainer. That's a no-brainer. I'm definitely going to go to you. Someone else in the ad board said the same as it relates to new-onset diabetes. That's essentially the education that needs to happen. It's not to pull people away and say, don't worry about LDL-C anymore. We feel very confident in regards to our ability to reduce that fundamental need in the marketplace. It's helping people understand that now there's a new bar for what efficacy means and stands for. Hi, Martz Adler Guggenheim Securities. Thanks so much for sharing these exciting analyses with us. I have two questions about particles. The first one, could you elaborate on why you believe LDL-P is more impactful than, say, for example, ApoB, where you see a relatively more modest impact on the data? The second question is about the small particles. Specifically, you mentioned a couple of times that you're relying on NMR as a measurement for particle size estimation. Can you comment on the use of that technology as opposed to, for example, ion mobility measurements? Looking back at NSHA-PIB, it was shown to preferentially reduce small LDL particles in an NMR-based study. Two studies using ion mobility in both healthy volunteers and patients showed the exact opposite preferential decrease of the larger particles. It would be great if you could just comment on differences between those technologies and why you rely on NMR. Ion mobility was invented by Ron Kraus's lab at UCSF. Basically, no human on the planet uses it anymore. It has gone completely out of fashion. I do not think it was based actually on much. The fact that when you do NMR, you are not only looking at proportion of particle numbers, but you also look at size. The LDL size in all our trials goes up. That is only possible if the relative contribution of larger particles becomes bigger. The observation, and that automatically means that smaller particles have to go down. There are two NMR platforms. One is the American platform. Jim Althus was actually the driver of that. Then there is in Europe the Nightingale platform, which is a Finnish platform that was used actually in the U.K. biobank for all the Mendelian randomization studies. There is a lot of internal and external validity that has gone into that. There has never been any mistake. I actually do not believe anything that is related to ion mobility anymore at all. Also, because the ion mobility predicted polydispersity of LDL particles. In that same article, they predicted that this would lead to terrible consequences for heart disease. What we saw in the NSHA-PIB outcome trial was a reduction in MACE. That completely did not coincide with each other. I would definitely start believing the NMR capabilities. Now, whether particle numbers are a better predictor of ApoB than ApoB itself has not been really settled. There are a number of examples where it definitely, I think six or seven trials where LDL particles were a better predictor than ApoB. There are also some studies that suggest that it is actually the same. That issue has not been entirely settled. What is very clear is that smaller particles, so when an LDL shrinks, the molecule ApoB stays on the particle. It needs to crinkle into itself in order to accommodate the fewer cholesterol molecules. It can only do so if it loses its sugar side chain. The molecule is heavily glycosylated when it is all blown up. It can accommodate a lot of cholesterol in a large fluffy, as we call it, LDL particle. Once it starts to shrink and becomes a small dense LDL particle, it has to lose its sugar. With that, it loses its mass. ApoB, the ELISA for ApoB, is a mass assay. Therefore, we think that if you lose all these small particles, your ApoB mass assay, your ELISA, underrepresents true numbers of ApoB molecules. That is why we think that LDL particles in that specific situation of a diabetic patient, but very high particle numbers on high dose statins, that actually small particles or total particles are a better predictor of risk than ApoB is. The regulators will just laugh us out of the room on any of these discussions. They want LDL cholesterol to go down. They have not arrived at this kind of discussions yet. It is all LDL. Maybe ApoB one day, but it will be a long time. Thanks. Thanks, team. Especially thanks for the exercise of explaining why you got 21% MACE reduction if you followed the linear regression. I'm sure investors have been asking you that. That math was helpful. I guess the question is, can you talk about what the contribution from those three are? If you look at that, right, like it's the strongest correlation to LDL-C reduction, then ApoB, then the LDL-C small particles. Which one is going to be the strongest driver in that model to give us MACE above 20%? That's sort of question one. Question two is interesting that I think we knew all along, right, through the data that diabetic benefit that obicetrapib has delivered. You're now designing the Rubens study. Why now, right? What do you hope to gain from a small patient study and why initiate it now? Like I think we knew a lot of the data and the benefits. Just the timing is interesting. You do two. Yeah. I'll do the first question. LDL is still by far the biggest contribution to the intermediation analysis also. That's by far the biggest contribution. In fact, officially in the mediation analysis, Lp(a) gets second. In the mediation analysis, the true mediation analysis, we cannot estimate the LDL particles precisely in the same analysis as LDL and Lp(a), because almost everyone gets dropped by 100%. We did the particle analysis at the end of the trial and not at day 84. You cannot officially do that. That is why we did the splines over age. I think that it is very reasonable to assume at least half of that effect is LDL cholesterol. Then comes Lp(a) and then third particles. To your second question, Yaz, there's really two reasons. One, you're right. We have data from Broadway that the diabetic, pre-diabetic population do have better LDL lowering closer to 40%. But those are sub-studies of a big study. In order to get new information on the label on a higher efficacy, this study would likely provide that higher efficacy in our label that we can then promote as opposed to a sub-study. That's one reason. The other reason is it's also not ASCVD population. It's primary diabetic population. To have that population in our label also expands the opportunity for the drug itself. It's really more about getting a broader label for that population. Also, we believe having a greater LDL efficacy for the monotherapy. It's also going to have the fixed dose combination in there too. It's going to be three arms. We get both, both of those versus placebo. Once the Kastelein and the MACE data is in the label, we can promote that study as well is our belief. Just to make sure, since you're saying it's going to be on the label, did the agency confirm that the study would be included? Or do you mean from a commercial perspective, you could publish it and have it in? Like I'm just trying to envision. Yeah. It's not something we can do until we file the efficacy. That requires FDA review. It's always a review issue kind of thing. Certainly the data in the publication is something that could be part of the value anyway. For us, it's expanding the population that we haven't studied directly before. Because everybody with diabetes pretty much had heart disease. We're looking at the pre-heart disease diabetic population, which is large. It's a large patient population. We have a question over there. Good morning. Nick Asik for Rowana Ruiz, Leerink Partners. Thanks for taking our questions. Maybe first circling back to stroke for a second. Any subpopulations within PREVAIL who might be more likely to show a benefit on the ischemic stroke component in particular? On the particle side of things, do you have a sense of what LDL particles are at baseline in PREVAIL? How it compares to BROADWAY? How might the 6% risk reduction attributed to LDL particles in BROADWAY translate to PREVAIL? The ischemic stroke question is interesting. I think obviously hypertensive, cardiometabolic, they're a higher rate of stroke. And we have even a little bit higher% of that in PREVAIL than we had in BROADWAY. That is hopefully a good high-risk group for measuring that endpoint. I think that addresses that question. Now, the other question about the part, you want to take that one, John, again? Yeah. So when you look at the baseline distribution of all the lipids and the presence of type 2 diabetes, et cetera, which will be extensively discussed in our baseline and design paper, of course, PREVAIL is slightly worse than BROADWAY. So the patient population is slightly more severe in that terms. So we expect particles and particle distribution to be at least as bad as in BROADWAY, but potentially a little worse even. In that sense, I think that that's all good. Now, of course, if you do a mediation analysis for contribution to a MACE reduction, as I explained to Jaz, what you need to have is the changes in a certain parameter between baseline and, for example, day 84, when only a few events have taken place because you want to link the event reduction to a change in a parameter. You cannot do baseline and end of trial because then most of the events will have happened. Actually, some patients will have died and gone off the trial. That you can do. A mediation analysis for a one-year trial is different than for a four-year trial. We can safely, I mean, the calculations that we presented today are checked and rechecked 500 times and by leading statisticians. I can vouch for that, that for a 12-month trial, 6% for particles, 5% for Lp(a) with a little variation at the top. When you add 9, 6, and 5 and 1, you actually end up at 21%. The numbers change when you do that for a full outcome trial. It is also in answer to your questions, Dennis, it's very hard to now predict. It will definitely have a contribution. You can't ignore that over and above LDL. To the extent of the number, it's almost impossible to say right now because the statistics will change in the mediation analysis. That's helpful. Thank you. Maybe looking ahead, how are you thinking about your future combination potential for OB with, say, other oral lipid-lowering therapies or mechanisms in development or even some of the oral obesity drugs in development? Anything you're excited about personally? We do see OB as a potential pipeline and a pill. I think what's great about OB, all those attributes we talked about on the efficacy, safety, LDL plus, manufacturing is going very well. The chemistry of it makes it a very easy small pill combined with any other pill. That value, we don't get a lot of value for a lot of things. One thing we don't get any value for is how good OB is to combine with anything else. We are looking at all kinds of opportunities. We are doing research and studies on that. As you may know, we do have a patent on SGLT2 OB combination. Obviously, GLP-1 OB would be a nice combination. We are looking into that. We are looking into these opportunities. It is still early to talk about. Vincent, by the way, was designed as a proof of concept of combining OB with a PCSK9 oral because it makes sense that if they have additivity on Lp(a) lowering, you can do the exercise of seeing how the profiles of the two drugs together would look exceptionally good. You have LDL lowering, Lp(a) lowering as one pill. We are considering that as an option also. Matt, yes? Yeah. Thank you. Matt Phipps, William Blair. Appreciate all of the in-depth discussion across a lot of topics here this morning. Two questions, if I may. One's a little bit of a follow-up. You all mentioned that the blinded event rates are kind of on track. Previously, you talked about looking at those as part of the decision on the MACE endpoint through four points. Did you look at individual components in a blinded manner as part of that analysis? Second, for BJ, I can appreciate the changing landscape in the prior situation and how that's all improving for brandeds. Talking to physicians, a lot still seem to have a Zetia step through in trying to get to branded medicines. I'm wondering if I know you want to place OB as kind of that second therapy post-statins. Do you have to think about, okay, maybe using that fixed-dose combination as a real drive of, okay, you're already on Zetia, you can actually get patient to that target by just changing the pill, still just one pill that includes Zetia, if that is kind of at least a bridge until maybe you can totally move them in front of Zetia itself? I'll do the first. Yeah, we did look at all the different types of events. Again, one of the things that at the FDA guidance is important to point out is that you just can't throw the kitchen sink in like you want to throw in all kinds of events. Because the events have to be adequately enough to say that the composite really does work. We have looked at the composite overall, the different four-point. They're all tracking well. I mean, we're going to have enough events of each people so you can make a substantive evaluation of each of the components for the composite. That's going well. That's one question. It's amazing that we've studied all the trials that have run and currently running is that once you know the total number of events that you expect in the four-point MACE, the ratio between the different events is extremely stable. The percentage of that, of non-fatal MIs, CHD death, and strokes is after a certain period of time almost the same if you look in the placebo arm of all these trials. We will discuss that in our baseline paper also. It's very stable. Once you know the total numbers at a certain point in time, you know your median follow-up, you can say, okay, that percentage of that total number will be non-fatal MI, will be stroke, will be CHD death. So far, it's tracking extremely well. Yeah. You don't want to handle the access one as well? I got it. I got it. No, it's a good question, obviously. I suggest we actually have data. I'll make sure I get it out to you. It suggests when you look at the landscape now, I know clinicians say they run into that step through of Zetia. It's actually less than 20% of plans actually have that step. The vast majority of the marketplace is open and allows us to do that. That's one. I would suggest to you, there are two things that make me feel very good about kind of our approach. One, in the dialogue and discussion that we're having in these PI dialogues, we're basically seeing, again, what is an acknowledgment of the value associated with our differentiation as a differentiated class. That in and of itself can give them a perspective to basically say that, well, we need to actually have access to this even in those more restrictive plans that may try to make you step through what would be a ZMI, one. Number two, your point is a good one. It is a leverage point for us if folks have to go through a ZMI to basically say, essentially, our pricing would be the same of OB and OB-EZ. It would be, if you will, kind of a low-hanging fruit opportunity for us. Great. I just want to let everyone know we only have time for about two more questions. We'll be around afterwards to take it. Here you go. Thank you. Good morning. Serge Belanger from Needham & Company. First question on the upcoming readout for the Vincent study. Can you remind us what you expect in terms of Lp(a) reductions here, whether Repatha should provide a synergistic or additive effect over the 45% that we've seen from OB's reduction? Secondly, regarding your regulatory strategy and potential labeling for obicetrapib, we spent the morning here learning about the different attributes of the molecule and it provides much more than LDL-C reduction. Based on your phase three program and BJ mentioning that FDA has been improving their labeling of their products, just curious which of these attributes you expect will be part of the label upon approval. Thanks. You should mind do Vincent. You do Vincent, yes. Vincent, that's the easy part of your question. I have honestly no idea at all. We actually don't even know how CETP inhibition lowers Lp(a) and we also do not know how PCSK9 inhibition lowers Lp(a). It's intuitive to think that it's removal, but there are countless arguments against it. No one really understands how it works. I cannot predict. We hope, because it's two such very different mechanisms, that there will be at least addition. I actually hope for a little synergy, because usually in medicine, when you approach a single target from two very different sides, you see at least additive and very often synergy. I personally think that there's a reasonable chance for synergy. From a scientific point of view, I couldn't answer your question because the mechanism has not been elucidated for either of the two classes of drugs. Michael will do the easy one. The labeling question is obviously something that we're going to work on with the regulatory authorities. Typically, they do allow for LDL, triglycerides, HDL, those things. Lp(a) has been in the label in Europe for inclisiran. That is one possibility. The FDA has not done that for any other LDL drugs so far, at least. I think we believe that the labeling sets the platform for the differentiation and how the drug will look from an efficacy and safety perspective. You build upon that with your medical affairs-related outreach, communication to KOLs and clinicians. We believe there's a lot of opportunity there to differentiate the drug, even if it's not in the label. Obviously, we're very careful about not doing off-label promotion or anything like that. This drug has, as we know for any other lipid drug, the effects are known among clinicians about what they do. That is basically, we are a science-driven company. We will get that information out there to the medical community through the typical educational programs and publications as well. If I may just add to that, Michael, if I may. Sorry. I'm going to stand just so I could see it. We will be extremely careful. Like our indication we believe will be LDL lower, and so that's the basis of the set of patients that we're addressing. Now, subsegments, patient segments within that, we think are completely fair to have a dialogue about and to talk about this patient profile versus that versus that as long as we're addressing what is LDL. To Michael's point, we would love for some of this information to make it into the label. If it's in what are strongly supported journals and there's consistent with label dialogue, that's the area of opportunity we see to be able to address this. To be very clear, we will stay as far away as possible, as you can imagine, from scope creep as it relates outside of that base indication. Thank you. Great. This is James from Stifel. Thanks for all the detailed discussion here. Just wondering if you can offer any color on how well or how closely you can track compliance and things like that in PREVAIL. Really sort of the genesis of this question is there's so much data that you just walk through around the strength of the clinical data, the trial design, et cetera. What do you think is kind of the biggest risk, if any, to kind of achieving a 20%+ MACE benefit, just given how compelling all of the data is here? Just curious if you have any thoughts. Right. You bring up the key thing, compliance in the trial, minimizing drop-in, drop-outs. Our team is exceptionally good. John and Doug and Mark are all over the world having investigator meetings to get everybody to promote the importance of adherence to the trial. We are looking, obviously, doing compliance checking and looking at all the different quality measures that we went to on these sites. The more we've put in more monitoring, we've gotten people engaged in going out to all the sites and making sure that the quality is maintained. Like I said, we're very happy with the quality of the study so far. We look at benchmarks of other studies that have been done, successful outcome studies. We are actually doing, if not as good, better than these other studies that have been done. We feel really good about the quality of the trial. We, again, hope to wrap it up just a year and a half from now. We'll be completing all the patient visits and so forth. Yeah. That's when we're finishing the trial. What's very helpful is that once you publish your phase three trials in such leading journals and you look in the side effect tables and there's nothing, that actually you can say at an investigator meeting, dear doctors, if a patient comes back in PREVAIL with a side effect, you can tell them it's nonsense. Because there are no side effects. Of course, you don't say it's nonsense. You actually point the and that actually is very helpful for getting patients back on drug. It's very different, of course, if you have to say, yeah, we have a phase three program. Ethically, we have to show you the side effect table. Sorry, but there's a lot of abdominal pain and gastroenteritis or whatever. It's very different. Those two papers in the New England Journal and The Lancet were extremely helpful in our investigator meetings across the world. Michael is exaggerating because Doug is doing all of those. I'm actually maneuvering myself out of the ones in Georgia and in Jordan. He's doing all of that. They're very successful. Yeah. Maybe there's one last point I would make on that before we close out the Q&A session is every level of control that we can exercise, we are. The conversations I have with Doug are, is there anything else you could be doing? Is there anything else we could be doing? Just to make sure that the strength and the balance sheet that we have, we're able to lever in what is our most important clinical trial. Michael mentioned the additional site visits. Just to give you a sense for what an example of one could look like, I know John and Michael and Mark went to China most recently. To have an audience, a ballroom filled with clinicians, investigators, and to have John and the team present the clinical data, I think there's no greater motivation than that. It's to have the data, but to have it be presented by those that know this field the best. Again, thank you for joining us today. You've been very patient with us. If you're able to join us for lunch, I do want to introduce other members of the management team that are here. Doug Kling, who's our Chief Operating Officer, but most importantly, who heads up clinical trial operations for us and can speak at length about what he and his team are doing to ensure the success of PREVAIL. Juliette Audet, our Chief Business Officer, whom I would hope you'd leave alone because she is not able to answer a lot of questions. We have Mary Allen McQuaid, who heads up HR for us, and our newest member of our executive team, Mike Marino. Adele Goff on our board is here also. Yeah. So excited to have her. You've shown incredible restraint. Nobody asked a question about Alzheimer's. We'll save that for lunch. Before we conclude, I do want to thank Matt Philipe. He has done an astounding job just as a conductor of this orchestra. We tend to go our different ways. This has been an awesome event. We couldn't thank him more. All right. Thank you.