Thank you. Happy to be here. Great. A lot of new developments with the company, including some updates to the PREVAIL trial. I thought maybe we'd start there. I guess based on what you're seeing out of the event rate for PREVAIL and what you learned from BROADWAY, can you describe maybe what drove some of the recent changes to the PREVAIL plan? Sure. I think it's important to provide a historical context. When we started PREVAIL, basically the same time as BROADWAY, we designed the two studies to basically have very similar inclusion criteria. You have to have established atherosclerotic cardiovascular disease, a high LDL above 100. If it was 70-100, you had to have other risk factors to get you included in the trial. We wanted to ideally have a higher-risk population that also was very amenable to LDL-lowering benefits. I think some of the lessons learned from previous trials is that the LDL levels are so low to begin with, you can't make much of a difference. Also, you just have to keep in mind that when you have a higher LDL baseline, you want to avoid the drop-in type of things, the placebo. You have to find the right kind of balance. At the time when we started, the guidelines really did not advocate for going on beyond adding statins to further control LDL cholesterol. We had a good time to start a trial that could achieve a higher LDL baseline. We also selected a four-point MACE as the primary endpoint that was historically used. The more recent trials have gone to a different four-point MACE that is more specific for LDL-lowering benefits. For example, in sort of cardiovascular death, which includes heart failure death, we limited it to coronary heart disease death, which is basically fatal heart attack, because heart failure is not modified by LDL-lowering therapy. We wanted to have a much more precise definition of who benefits from LDL-lowering therapy. The non-fatal MI, that's always a standard endpoint, non-fatal heart attack. You have stroke, and stroke is, again, hemorrhagic stroke is not benefited by LDL lowering, but ischemic stroke is, and it does take longer than other risk factors, other endpoints to be modified by LDL lowering, but over time, it becomes a very strong contributor to the benefit of LDL-lowering treatment. The last, which is the most variable across trials, is the revascularization definition. An urgent revasc is what we initially chose. We then learned through other trials that the total revasc is actually just as good as far as the relative risk reduction as the urgent revasc is. That's because care has changed where in order to get a revascularization, you have to have evidence of ischemia or symptoms. In the past, that wasn't quite as challenged by payers and so forth. Now you have to have a real strong reason to get a stent put in, which made urgent revasc much more consistent with LDL-lowering therapy. The recent trials like FOURIER and VESALIUS-CV and CLEAR Outcomes all use the total revasc definition. We looked at that standard definition, which is considered what's called the CTT Collaboration line definition, a 4-point MACE in BROADWAY, and that's where we saw the 0.79 hazard ratio. With that more precise definition, also providing a lot more events, because total revasc provides about 20% more events than just urgent revasc overall. I think we announced just about a year ago that we're changing our 4-point MACE from this older 4-point MACE to the newer, which is being more widely adopted across most clinical trials. That was part one, the historical context of why we decided to do the interim analysis was really for two reasons. One is we also decided because of just our own view that we have to have a positive trial for this drug to be successful. We don't want to take any chances on the drug not being successful in the outcome study. Nothing's more important to NewAmsterdam than success of PREVAIL. We had originally powered the study for a 20% relative risk reduction, and now we want to power it to a 15% relative risk reduction for the primary endpoint, more than 90% power for a 15% relative risk reduction. We did have the more events due to total revasc as opposed to urgent revasc, but we also wanted to increase the number of events significantly more beyond that to make sure we have a 90% power for the 4-point MACE at the end of the trial. That would be another year of follow-up to achieve that greater magnitude of 4-point MACE. In the meantime, though, we also noted that even though the event rates were tracking exactly in line with BROADWAY in PREVAIL, which was a great sign because that had a 21% relative risk reduction in that same composite 4-point endpoint. We also noted that in year two, and now even more so in year three, the event rates are dropping. You can estimate your placebo event rate in two ways. One is you get a predicted placebo event rate based on a lot of other trials that have been done, and there's been 15 other outcome studies done in the last 10 years. You know what the event rates should be, especially three-point MACE events across all these different populations. You can model things based on their risk status. More importantly, we have BROADWAY, again, a very similar study population. You have a good sense of what your placebo rate's going to be in PREVAIL. There is a natural decay that can occur from year one to year two, but this is even more than expected decay. In light of that, we believe we have a good chance to see a positive benefit at the interim analysis, which is still more events than we originally planned to stop the trial at the beginning, to see a significant benefit, and we've powered for both 4-point and 3-point MACE. If we're achieving a benefit comparable to the 0.79 for both 3 and 4-point MACE, the study will be stopped for efficacy. Our alpha spend is minimal. We markedly increased the overall success of the trial probability by making the number of events much greater than we originally planned, but also because of what we're seeing trend-wise in the data, the blinded data, the blended blinded data, we feel that we have a good chance with the interim to keep us on that same timeline that we had originally planned to finish the study. Yeah. That's a long explanation to your question, but it provides a lot of context to the history of where we started, what we've identified through the BROADWAY data, and what we're seeing in the blinded data to date to give us the high confidence that interim is a good idea to do. Yeah. I think trying to analyze blinded data can be a bit of a dangerous game at times, right? Can you just maybe elaborate a little further on what gives you the confidence that those blinded event rates are separating according to what you'd expect from either historical modeling? I'm also thinking about the fact that BROADWAY, as you mentioned, it ended at one year, right? You don't necessarily have that bridge to sort of the duration that you have in PREVAIL. If you could just talk more about what's underpinning the blinded event rate confidence. Right. We looked at many different ways of thinking about it. 1 is that we know the very well-established association between LDL and cardiovascular events. We know what our LDL delta was in BROADWAY, and that translated to a 21% relative risk reduction. We don't know, of course, we're blinded to the LDL delta in PREVAIL, but we know it should be actually a little bit better than BROADWAY because it's a little bit higher baseline to begin with. We know the correlation between LDL lowering and events, and if that correlation holds up, the outcome study, the interim should work. It should stop the trial based on LDL lowering at that time point. That's based on using established LDL lowering benefits. That's number 1. Number 2, in the REVEAL study, which was the Merck CETP inhibitor in their upper tertile of non-HDL cholesterol, which is 10,000 patients, very similar in size to BROADWAY, to PREVAIL. The 10,000 patients in PREVAIL match very well the 10,000 patients in the upper tertile for REVEAL, the Merck study. In that 10,000 upper tertile, they had a significant difference in events at 17%. That was very encouraging. Plus, we know our LDL non-HDL lowering is going to be quite a bit better than what we saw with anacetrapib. That was, again, a subset of patients that in a bigger study matched, but that also would be enough to stop the trial at the interim. Okay, that would be the type of benefit that we know that we'd be 17+% because of what we saw in the REVEAL study. We have the historical event rates, especially 3-point event rates are very consistent across all trials. It's the easiest things to adjudicate, non-fatal MI, CHD death, and then stroke. Those 3 things are most consistently adjudicated, and we're seeing, you track over years these event rates in all these other trials, you have that data available to you. Our event rates are consistently lower than what those event rates were in those 15 other trials. We have the BROADWAY data. Again, the first year event rates were identical in BROADWAY to PREVAIL 1st year across all the composites. When identical, almost identical. CHD death, non-fatal MIs, revasc, urgent, elective, everything looks very closely similar in the blended event rates versus the blended BROADWAY rates. In year two, that gives us confidence that that 21% that we saw in BROADWAY could also be seen in our PREVAIL first-year data. In year two, we expect some decay in that event rate, but it's much more than expected. We looked for all kinds of reasons, drop-in, GLP-1s, or PCSK9s, and they're just not there. We don't see drop-ins to these other therapies that could affect the placebo event rate. We have a really good idea what the placebo event rate should be, and we're seeing, again, low event rates that gives us optimism, encouraging signs that the interim should stop the trial. Got it. If not, we still want to make sure at the end of the day that we have a very well-powered trial to make sure we get a positive outcome overall for obicetrapib. Got it. Maybe said another way, there was originally a timeline plan for PREVAIL, and it sounds like what you're saying is everything on the placebo arm is tracking with your expectations, but perhaps the drug is really driving a benefit, and that's why you need more time to accumulate some of these events. Right. Is that the right way to look at it? Also add a lot more events to the end also. We went from 1,000 to another much larger number. It's both the lower event rates and the fact we added a lot more events to complete the trial. Yeah. The interim also includes the 3-point MACE that you referenced. I guess why add that as a requirement to pass the interim, and why is that maybe not required for the final analysis? Well, the interim is to stop early, right? To stop early, you can have a very significant P value for 4-point MACE, which is great, but if you had a study that had a 4-point MACE that was great, but the 3-point MACE didn't quite reach statistical significance, that would be criticized. It would still get you on the market. It would be approved, but you would be criticized for not having the hard MACE, and that affects a lot of things. We don't want to take that risk. We're going to make sure that the 4 and the 3-point are both significant before we stop a trial. Again, by the end of the day, our main objective is to have a positive trial for both 4- and 3-point MACE. Yeah. It really comes down to, I guess, physician interpretation of the meaningfulness of the revas. Right. Exactly right, yes. The revas alone being a driver of the benefit without a statistically significant 3-point MACE, it hasn't been seen before. We feel, again, of all the events that are dropping in the second year of PREVAIL, a bigger contribution does come from the 3-point MACE. That gives us, again, more optimism that we should hit both the 4 and the 3. We can't have a study stopped early, if 3-point MACE is not also significant. The overall benefit of the drug academically or commercially would be affected. Yeah. BROADWAY showed clearly very impressive benefits- Right -on MACE. It sounds like you guys are pretty confident you can reproduce that, and you also mentioned that hitting on PREVAIL is really important. You also mentioned that the powering at the end of PREVAIL is going to be for 90% for 15% MACE reduction. Right. BROADWAY showed 20%. Right. PREVAIL's a longer study. It's got potential to do even better. Why such conservative powering? Well, if you look at all the other studies that were done, all the lipid trials that have done in the past 15 years, the range of relative risk reduction was 9%- 19%. No one hit 20%. That would be the best of any trial recent, in the last 15 years. It's our conservatism. Like I said, we only have one chance at this, and we don't want to lower the chance. The most important thing for us is a successful trial. I know some people may argue time is a big issue, but for us, we have the funding to do it. We want to take it all the way to the end, give the drug the best chance it can to be successful. Yeah. I know you guys try to be data-driven, and we try to be data-driven, but as we think about the data from obicetrapib, what in the trial design do you think could cause it to not end up reproducing the benefits that you saw? The biggest issues that, and we're very on top of this, is drop-in, dropouts. Dropouts, loss to follow-up, and drop-ins on PCSK9s or GLP-1s or SGLT2s or any of these other drugs that affect cardiovascular. We feel really good about the quality of metrics of all those things. We're of course worried about when new drugs are put in the market, like an oral PCSK9, we want to make sure that we don't affect the quality of the study. What we're encouraged by it is that all those things are in low single digits, which is a really good point. Those are all good quality metrics for all those things. Our dropout rate and loss to follow-up is lower than any other contemporary trial to date. We have a great team working hard on making sure people stay in the trial. I think what we don't give enough credit to is the drug itself. Obicetrapib is so well-tolerated, and the BROADWAY data were so impressive that I think investigators themselves were highly motivated to keep people in the trial because they're not having any complaints, no side effects, no great Phase III data. That always helps to keep people in a long-term study with us. Can you also discuss the regulatory side of this equation? It's a Phase III trial that had some changes to the stats plan. On one hand, hitting on hard endpoints feels like it should be a no-brainer. I guess, how much consulting with the FDA was this before the changes were made, and I guess how confident are you that a hit on either the interim or the final analysis here will be acceptable? We're working very closely with the FDA. They're well aware of all our changes and so forth. It's moving along fine on all that process. We really feel good about our interactions with the FDA on this trial. We're working together to basically get in line with the fact that we want to have the outcome study available at the time of the drug launch itself. In fact, they appreciate that we will be the first LDL drug launched with an outcome study data in hand at the time of launch. Yeah. Can you file just ahead of the interim, or would you wait for the interim to turn over? We haven't disclosed that, but we're looking at all these different options. Got it. How do you think about, this is another topic that comes up frequently, the Lp benefit of obicetrapib and sort of the evidence that may emerge later this year about what Lp contributes to residual risk? Right. I think, obviously, Lp is a very important causal factor. We're encouraged by the 50% Lp lowering that we get with obicetrapib in that 50-150 nanomole per liter range. What's great about where obicetrapib fits in is it won't actually compete with the injectable therapies because they're going to be relegated to the 150- 200 nanomole per liter higher patient population that have existing heart disease. We're going to be the therapy for those that don't yet have heart disease. They won't qualify for. I think the injectables, they're planning them to be quite expensive. They're going to be basically premium-priced. They were designed that way in their trials. We would be the drug to go to for anybody that has a 50-150 nanomole per liter Lp(a). If they don't have heart disease, we'd be giving it to everybody that has high Lp(a) because they don't have the option of having the injectable if they don't get heart disease. That creates a large number of patients out there that are going to want to gravitate towards obicetrapib as their add-to drug for statins, or even replacing statins for some people that have high Lp. One thing the Lp people know, a lot of them know, is that statins raise Lp, and they want to avoid a drug that raises their Lp, even though we know that LDL lowering still benefits those patients. We think we have a really good message for those patients. With HORIZON coming out, the best-case scenario for us is it works, and it works well, and Lp lowering is established, and we have a drug that would be on the market, if not at the same time, actually earlier than pelacarsen. If it shows a benefit but doesn't quite hit stat sig, that could even be a better scenario for us. We'd be the first Lp drug on the market with no other competition. Either way, any of those scenarios work well for us. Even if it doesn't work at all, and there could be other reasons why it doesn't work. The study had whatever, the dropout, the injectable inflammatory reaction every time you inject. All these things could be a reason why Lp lowering with ASO is not effective, but which I doubt is going to be the case. It's already passed two interim analyses. We already have our own data with BROADWAY showing the 21% relative risk reduction, and PREVAIL itself, will be available at the time of launch. There won't be any belief that this requires Lp(a) lowering to be effective. It's all based on its own intrinsic benefit that it has from its own data. We believe that will be something that it's not going to interfere with our ability to market obicetrapib as a very effective therapy to lower cardiovascular events. Got it. I want to touch on one last topic in our last two minutes here. There's always still some debate about do we need more LDL-lowering drugs or not? I mean, you're a physician, I guess, how do you think about prescribing LDL-lowering drugs? What's going to drive that patient's residual risk? The MACE benefit, the actual LDL lowering? Is it any of these ancillary benefits that obicetrapib comes with? I think the great thing about the new guidelines that came out is we're finally back on track with lower is better and getting below 55 for a lot of patients. Even the concept of starting a drug earlier in life can make a huge difference long term. Why wait for the heart attack or stroke to start lowering the LDL? What people are seeking are better ways to get LDL below 55, which is obicetrapib is a perfect option. Oral, well-tolerated, has all these other ancillary benefits which really motivate patients to get treated, including APOE4, high risk for Alzheimer's prevention, Lp(a), diabetes. Now for those that don't yet have heart disease, and getting earlier in life, we believe the profile of obicetrapib is going to be very appealing to those people because it doesn't increase the risk of diabetes. It decreases the risk. It lowers the Lp(a). It has this potential benefit on preventing Alzheimer's disease. We believe as people start thinking about why wait for the heart attack or plaque to start treating with an LDL-lowering therapy, especially a statin, why not go with obicetrapib? We see the opportunity is really great for the add-on to statins and secondary prevention, as a primary prevention drug, we'll have evidence of benefit, again, statins will be the mainstay. For a lot of people, that won't be enough, or for a lot of people, they're going to prefer obicetrapib. Again, they have to deal with their payers and their doctors about that. We believe it'll become a very important drug in the whole armamentarium of lowering LDL to reduce risk. We think the future is lower is better, but also starting younger in life is better. Having an obicetrapib profile is going to be really appealing to both clinicians and patients. Fortunately, that's all the time we have. Thank you so much for joining us. Okay. Thank you.