NewAmsterdam Pharma Company N.V.

Good day, everyone. My name is June and I will be your conference operator today. At this time, we would like to welcome you to the new Amsterdam Prevail update call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, and if you have joined via the webinar, please use the raised hand icon, which can be found at the bottom of your webinar application. At this time, I would like to turn the call over to Matthew Phillippe, Executive Vice President, Head of Investor Relations.

Thank you, and good morning, everybody. Thanks for joining our call today. I'm excited to have Michael Davidson, CEO, John Kastelein, Chief Scientific Officer, and Ian Samaya, our Chief Financial Officer, on the call today. The presentation we'll be discussing is available on our investor site, so please feel free to access it there. However, before we begin, I let Michael share some exciting news. I would like to remind everyone and direct everyone to slide two and remind that this call will contain forward-looking statements within the meaning of federal securities law. These statements may include but are not limited to those related to potential clinical benefits of our product candidates, our clinical trial progress and design, and our expectations regarding the contemplated interim analysis of our prevailed trial and trial completion. Each of these forward-looking statements is subject to risks and uncertainties that could cause actual results to differ materially from those in such statements. These risks and uncertainties are discussed in our annual report on Form 10-K filed with the Securities and Exchange Commission on February 18, 2026, and in subsequent SEC filings, including our Form 10-Q for the quarter ended March 31, 2026, which we're filing with the SEC today. Our filings are available at sec.gov and on our website, newamsterdampharma.com. Except as required by law, we assume no obligation to update forward-looking statements publicly, even if new information becomes available in the future. With that, I'm excited to present and introduce Michael Davidson, CEO of New Amsterdam. Michael.

Thanks, Matt. Good morning, everyone, and welcome to our Prevail Update call. Today I'm excited to provide an update on the clinical development of Obacetrapib, including the latest timelines for completion of the PREVAIL trial. We recently marked the two-year anniversary of the last patient enrolled in PREVAIL, and have observed some encouraging trends in the blinded data. As previously disclosed, the first year blinded event random prevail is tracking in line with what we saw on Broadway, which John will discuss in more detail shortly. This is consistent with the intent of the design of this trial. Importantly, the year one to year two overall MACE rate has been lower than anticipated, a trend we find encouraging when viewed against historical LDL-C outcome studies in this population. As a result, we have decided to conduct an interim analysis in the fourth quarter of 2026. This timing aligns with a minimum 2.5-year follow-up for the trial, and we expect results in the first quarter of 2027. Should the trial not stop for efficacy at the interim, we continue to anticipate completion by the end of 2027. With the recent expansion of the primary endpoint of MACE4 to include total coronary rather than urgent revascularization and an expected median follow-up of nearly 3.5 years, the interim analysis will now occur with substantially more events than approximately 950 events we had previously projected. This gives us a statistically more power for the primary 4-point MACE endpoint, but the statistical power to detect a 3-point benefit remains unchanged. In Broadway, we observed a 0.79 hazard ratio for the exploratory MACE 4 endpoint. Should we see a comparable hazard ratio in both May 3 and May 4, we will be well-powered to detect the difference at the interim. These data remain preliminary as we continue to complete adjudication of year two events, but they signal a potentially meaningful and encouraging trend. We look forward to sharing additional details at our annual investor day on August 5, 2026. With that, I'd like to turn the call over to my dear friend and colleague, John Kastelein. John?

Thank you very much, Michael, and it's very good to have everyone on the call today. Now, as Michael alluded to, we have very exciting observations from our initial appraisal of the two-year blinded data in Prevail. But before that, I would like to go back and talk about what happened in Broadway so that everybody understands the premises. If you recall, we saw a 21% reduction in our predefined exploratory MACE4 endpoint that we could attribute to multiple factors, including LDL particles, lipoprotein little a, and there is some room for potentially other factors such as less new onset type two diabetes. If we move from the Broadway slide to the next slide, you can appreciate the separation of the Kaplan-Meier curves around day 200, which is a rational and a biology-based response that we have seen also in other outcome trials, where the curves are together, basically superimposed on each other until six months and then separate. To further corroborate this, on the right hand on the slide, we show a landmark analysis that starts at the six-month mark that shows a clear separation of the two curves along the full second half of the first year. Now, if we combine this data with the data in Brooklyn, our other phase three pivotal registration trial, these data in fact become statistically significant for the separation of the Kaplan-Meier curves. What's very important and is on the next slide and for us is an important basis for everything is the similarities that exist between Broadway and Prevail. We have to remember that Michael and I designed Broadway to be a mini Prevail in order to provide us with the information to make changes to the Prevail design if needed. Fortunately, in that sense, we now understand that we have very similar baseline characteristics between the two studies. The baseline LDL, very importantly, is around 100 for both studies, and in fact, a little bit higher in Prevail. In addition to higher baseline, slightly higher baseline LDL cholesterol, Prevail also has more type two diabetics and more post-MI patients than Broadway. And therefore trial logic dictates at least similar or slightly higher ASCVD risk in Prevail than in Broadway. And we will see later that that is corroborated by the data. But next to the baseline characteristics, it's also very important to remember that these trials were started basically at the same time in many of the same geographies, in the same sites, and also with the same adjudication committee for events. All these characteristics ensure that Broadway is a almost perfect comparator to prevail And the fact that we already saw a 21% reduction of the four-point maze in Broadway makes all of this, of course, very exciting. Now, to move further, as we disclosed earlier this year, ASCVD events in Prevail, in the first year at least, are trending in line with what we have seen from Broadway. And now if we go to the next slide, here's actually the exciting and visual representation of this. In fact, this is exactly what we would hope to see because Broadway and Prevail for the first six months are basically on top of each other in terms of their KM curves. If not that Prevail actually is slightly higher, which would be supported by the observations of the baseline characteristics. Now, when the Broadway Kaplan-Meier curve splits, Prevail stays right in the middle of those two lines, which is extremely encouraging given that we wouldn't expect the two to be any different given the similarity in trial designs. In fact, the Broadway placebo arm continued its upward trajectory, as would be expected in such a trial, and the active Obesetrapib arm started trending downwards, which is exactly what we want to see. So to us, this analysis is an extremely powerful visualization that we are seeing similar event curves in PREVAIL than we have already seen in Broadway. And highly important, we believe that with this, we have excluded that Prevail has in any way enrolled an outlier population that would not meet our normal analytic standards. Now, as Michael alluded to already in our initial review, we have seen a continued trend downward from the one-year mark to the two-year mark. Based on the trend we observed in Broadway and the slowdown in events from year one to year two, we are optimistic and excited that this is being driven by a treatment effect. In my experience of the steering and executive committees of numerous lipid lowering trials in this area, this kind of slowing of event rates is very exciting and compares favorably to trends in other lipid lowering CVOTs that I've been involved in. Now, of course, as Michael also alluded to, this is an ongoing trial. There are still, I mean, There are still undoubtedly a few events to adjudicate, and we will have the additional updates at our investor day in August. But nevertheless, we are very excited now about how things are going. And of course, this is the main reason to bring in an interim analysis, as it allows us an opportunity to validate the observations that we shared with you, and if not, continue the study to the end with sufficient power to have a successful outcome. And with that, I'll turn the call back over to Michael.

Michael, your line may be muted.

Thanks, John. As John just presented, we continue to see encouraging trends in PREVAIL, and now, with a planned interim analysis, have additional chance to stop the study. Based on the trend we observed in Broadway and the slowing of events that have been seen from year one to year two in the blinded prevailed data, we are optimistic that this is being driven by a treatment effect. With that, I would like to open the calls for questions. Thank you.

We will now move to our question and answer session. As a reminder, if you have joined via the webinar, please use the raise hand icon, which can be found at the bottom of your webinar application. When you are called on, please unmute your line and ask your question. To allow time for as many questions as possible, we ask that you please limit yourself to one question. We will now pause for a moment to assemble the queue. Your first question comes from the line of Yasmeen with Piper Sandler. Please unmute yourself and ask your question.

Hi there, sorry, can you hear me?

Yes, yes, we can hear you.

Okay, sorry about that. Hi, this is Shannon on for Yasser Hemi. I had a little bit of trouble with you on mute, but just two questions for us. Thank you so much for the update. About the interim analysis, could you speak a little bit more about why for Q26 and maybe the timing on that and whether you think the interim analysis might be able to impact the statistical plan if there's any concern about a penalty there? And then just about Pella Carson's Horizon study coming out in early to half 26. Can you talk a little bit more about potential read through to prevail and their expectations there? Thank you.

Sure. I'll start. I'll turn over to John a little bit also. But so 2026. For those that are familiar with the trial design, we had a two-and-a-half-year minimum follow-up, and that's the timing of that. So that's part one. But also, we'll have... You know, enough events at that time, especially four-point MACE, which we've discussed, will be actually substantially more than we originally had planned for the final analysis of the trial. And MACE 3 events that are comparable to what we're going to have at the end of the trial. So we thought this was a good time to... to provide an air analysis, especially in light of the fact we're seeing these very low event rates compared to Broadway first year events, prevail first year events, the events are coming down. So it's a very encouraging sign. And so we will be powered sufficiently to see a comparable, you know, 0.79 hazard ratio for both in the MACE-3 and MACE-4 to be powered well enough to see a benefit there to stop the trial at that point. So that we felt was a win-win situation for us. We have a chance to stop the trial in early 27, but we're still without... we'll go into more detail at the R&D day, but we, investor day, but we have Our desire is to make sure that we have very sufficient power at the end of the trial to be in the same relative risk reduction that we've seen with the recent LDL lowering trial. So we want to make sure the study overall is still very well-powered to achieve that result at the end if the interim analysis doesn't stop the trial. But like I said, we're very encouraged by the interim analysis results. probability of success. We're trying to look at that as a win-win for us at that time. So, regarding Horizon, I'll turn that over to John to answer that question, because he was very involved with that study prior to his role with New Amsterdam. And we can give you a little bit of insights from what we understand about the biology of LPLA as well to address that second part of your question. So, John, I'll turn it over to you.

Hi. Jasmine, this is John. As you know, in our Phase III program of Ovisetrapib, we have shown that 10 milligrams once a day actually lowers lipoprotein little a by 45% to 50%. in the range between 50 and 115 animal per liter, which, by the way, was just today accepted as a paper in the European Heart Journal. I just got the email this morning, totally coincidentally. So that is now peer reviewed and will appear soon in the European Heart Journal. Now, of course, the read-through of that effect to an outcome effect is very hard because there are no outcome trials yet. So what we feel is that if Horizon reads out and gives us the relation between lowering of LP little a and reduction of ASCVD events, we can use those data to make the translation what that would mean for Obesetrapib in the Prevail trial. That, of course, only happens if Horizon is positive. And that is, of course, something that we, from a biology standpoint, all strongly believe in. And I think that the epidemiology, the genetics, and the Mendelian randomization is extremely strong for LP little a as a risk factor for heart disease. But it is the first trial. It is not the most potent LP little a lowering drug out there. And you never know, you know, that there's always stuff that can happen. But I think the biggest chance is that Horizon will be positive and that we will get a read-through. In case that horizon is not positive, it doesn't matter much for us because we still have our 21% MACE reduction, our exploratory MACE 4 endpoint in Broadway. And then what is very likely is that the contribution of particles and diabetes, et cetera, actually is larger. So for us, a negative outcome of HORIZON would actually not be a problem at all. But, of course, we all hope, and I personally hope that also for patients, is that HORIZON will be positive. And then the read-through to Ovisetrapib is very clear.

Let me say one other comment to that, because we all hope LP light lowering with Pellicarsen is successful. But remember, they have, I think, 990 events. At least that's what they proposed in their design paper. Again, we're going to have more than that, well, more than that at our interim analysis. And so they've had two previous interims, which did not stop the trial for futility. There's also a chance the study shows a benefit but does not achieve the cystical power, the p-value for approval. Or there are side effects, but whatever. We know the platform itself, you do get certain side effects, skin reactions, and so forth. That will make the therapy either positive. not very popular or not necessarily approvable, at least with this particular therapy, because there are many others to follow. So we're very excited about LPL-A lowering in general, but that could put us as one of the first LPL-A drugs, although we're not indicated for that, could be one of the first oral therapies to lower LPL-A in that 50 to 150 range. you know, by approximately 50%. So we feel that a study that may not, it's positive, great, that's fantastic for everybody. If it has a relative risk reduction that does not achieve approvability, that's also great for us. So we think it's a win-win, again, across the board. You keep using that term, but we feel that the Horizon trial will be very, very helpful to us no matter the outcome. And so we look forward to seeing the results relatively soon. So next question.

Your next question comes from the line of Tyler Van Buren with TD Cowan. Please unmute and ask your question.

Hello, can you hear me? Yes, Tyler. Wonderful. Good morning. Thank you so much for the thoughtful presentation. As per usual, I'll do my best to stick to one question here. So regarding the year one to two event rate being lower than expected compared to historical trials, Can you elaborate specifically on what trials you're comparing to and your confidence in that analysis, given that the comparison is to trials in the past and standard of care potentially might have changed since then?

Yeah, thanks, Tyler, for that question. So we've done a lot of work using AI technology. We can model very well the outcomes from all the other trials that you could adjust for their LDL baselines, their percent diabetes, their percent with post-MIR stroke. and so forth, and age, and all so forth. And also, we also, of course, adjusted for the add-on to GLP-1s and SGLT-2s, which, by the way, we've had very little add-ons in our trial. We keep making that point. I know people worry about that, but we're tracking that. PCS canines as well. We're tracking all the different add-on therapies that could affect the results. And we're very encouraged as well by the quality of the study, the low dropouts, the low drop-ins. We're exceptionally pleased by our quality metrics in Prevail, which again, that's the biggest factor we have to consider. When you do AI modeling for all the trials that have been recently done, you can list them all, you know, Fourier, Clear Outcomes, the Versalius trial, the, the Versalius doesn't really a little different because it's a primary prevention trial, soul select all these other trials that have been done recently that just completed. You can model very well what the placebo event rates will be. And so we we've done that and we hope to share more at our investor day in August. But also we of course have Broadway, you know, Broadway being the, the, you know, the many prevail, it gives us a very good prediction of placebo rates in prevail. And so when you do that and you, and you see the event rates that were blended events that we're tracking in, in prevail, we're, we're very encouraged by that. We're very encouraged by that. And so that, that gives us the, the, the belief that an interim is the right thing to do to maybe get this study done ahead of schedule, but we still don't want to in any way jeopardize the overall powering at the end of the trial, which we want to make sure that we do get enough power to achieve a benefit that we've seen with other lipid lowering trials, which is closer to that 15% range, you know, Fourier, Odyssey outcomes, clear outcomes, you know, Even Versalius had 19% in their four-point MACE. So we want to just, we're very encouraged, we're very excited about what we're seeing, but we don't want to, we have one last chance at a CETP inhibitor trial. We don't want to in any way jeopardize those chances. So I think an interim is the best way to go because we're so encouraged by the data. But yeah, we still want to continue to a maximal powering to make sure we can achieve the benefits that have been seen in other lipid trials recently.

And we have made very sure, Tyler, that the standard of care, because that's, of course, the very intuitive first question that you would ask, has basically not really changed. And also, please, I think we need to acknowledge that a minority of patients were US. So actually, the majority of patients came from geographies where the standard of care actually has hardly changed in the last decade. And that also contributes. And then, of course, Broadway. So we have three, four, five points to indicate that our population is very well treated, but still it's a very high risk population. And we see the actual numbers for the first year in Broadway. When we compare that, you know, the lines in that slide are completely on top of each other for the first six months. And so we have, of course, have thought long and hard about your question and have come to the conclusion that that is not an explanation for what we're seeing.

Your next question comes from Ruana Ruiz. Your next question comes from Rowana Ruiz with . You may unmute yourself and ask your question.

Hi, this is Michael on for Rowana Ruiz at Learning Partners. Thank you for taking our question. So when you report the interim results in 1Q27 and if Prevail does not stop for efficacy, what specifically gets disclosed and how should investors think about continued outcome. Is that neutral or could the magnitude of the trend that interim itself be informative for the final readout? Thank you.

So if the interim doesn't stop the trial, we won't know anything other than that. The study will continue. In the DSMB, they do have stopping rules for the trial. We will not be disclosing exactly what those are, but they do have stopping rules. So that's all we'll know. It wasn't stopped for efficacy or futility. And so we continue on, and then we continue on until we get the full event rates that we project for 2020. powering the study, you know, down to the typical, you know, 15% hazard ratio that have seen in all the most other lipid trials. So that's kind of what we're going to know. We still could achieve much higher than that. at the end of the trial, because that's how things go. But that's all we're going to know at that point of the study. Is that the question you're asking? We're not going to know anything more than that.

The related question, Michael, or the follow-up was, how should we think about the end of the study if the interim doesn't hit? And really the point there is we'll have much more statistical power going to the end of the trial not only for the primary endpoint, which is the MACE4, but all the secondary endpoints, including the hard MACE endpoints, which obviously have benefits from a labeling standpoint. So the overarching goal is to ensure the trial succeeds, and we have two time points we feel confident in being able to do that. And I did want to address one of the earlier questions in terms of how to think about the statistics. there is a minimal statistical penalty for doing the interim analysis. And that also informed our decision.

Next question. Your next question comes from Dennis staying with Jefferies. Please unmute your line and ask your question.

Hi, good morning. Thanks for the update. So you've previously said that for prior CVOTs, the trials failed the drug and not the other way around. So I guess, what are some of the pros and cons that you considered in doing this interim analysis, which potentially pulls forward the data by about a year, but at the expense of statistics? And as a quick follow-up, how should we think about the filing strategy, assuming the interim was positive? Did you meet with the FDA on this plan? And did you get buy-in from the FDA. Thank you.

Thanks, Dennis. So yes, of course, this was a decision. I think what was, again, the driving factors were the fiscal penalty is minimal. So there's really no major risk there for the overall trial result. uh and and secondly we would not be doing this unless we saw something really encouraging already that that's the key things that we're we're trying to get out to the medical community the investor community this is based on being the data that we're seeing like i said we look at this many different ways many trials trying to see whether the event rates that we're seeing can somehow be affected by other factors, but we just don't see any other reason. The most likely reason, we believe, is the drug is working and working well. So that means we want to have the The interim analysis, again, as we've been saying already, it's still more power than we had originally for MACE 4 and no different for MACE 3 for the trial completion. So in that sense, we believe we're not taking a significant risk. And we do have, obviously, the chance to keep going if the interim is not successful in stopping the trial. And that provides an entry to the market roughly one year earlier than the than otherwise. So that's a big factor, especially considering we think this drug is great. We want to get it to patients as soon as possible. It will be available in Europe. And so we feel that the interim is the right plan for the company and for what we want to deliver to patients with Obacetrapib. regarding the fda we are we are we are working closely with the fda on how to think about uh the interim and and how to uh apply that to our filing timelines but that that discussions are are are in play and we'll get more details to you after uh in august uh fourth august fifth uh and investor damien will provide more details on that but those discussions are presently ongoing yeah importantly we can say that uh

We also obviously submitted the trial amendment to IRBs, which several have been cleared, and those changes are now in place.

Your next question comes from James Condulous with Stiefel. Please unmute your line and ask your question.

Hey, thanks for taking my question and congrats on all the progress. I just kind of wanted to clarify, is sort of as it relates to this interim, the minimum effect size you're powered for, sort of like the minimum stopping criteria, is that the like 20 to 21% base? Or, you know, what happens if you show like a 15% base benefit in this interim? And then two, just a quick kind of clarification on these other trials. Is there like a couple, you know, one or two key trials that you think are good analogs for declining event rates that were, you know, an encouraging sign? Or do you think kind of all of these trials, like all the PCSK nines, et cetera, all sort of follow this trend that have had positive outcomes? Thanks so much.

So, John, do you want to take that? So I think.

Can I start with your second question? So in many trials, there is what we call a natural decay rate. So there is a kind of slowing of events in the placebo arm. But with AI, you can build that into your models. And so if the reduction in event rates you're witnessing on the basis of blinded data exceeds the decay rates that you've seen in former trials, then like Michael said, the most likely explanation for that is in fact that the drug is working and is working well. Now, there are differences between trials. For example, the decay rate in Fourier was larger than the decay rate in Odyssey outcomes, for example. But, I mean, those are, I think, details. And the CTT meta-analysis has shown us that for these lipid-lowering trials, it is hard to go by a single trial. So it's much more prudent to actually... Take a whole host of trials. And by the way, not only PCSK9 trials, because if you want to assess the decay rate in placebo arms, you can also look at GLP-1 trials. And you can look at a benpanoic acid trial and look at the placebo rates year one, year two, year three and everything. And I can assure you that we've done that in exhaustion. And we've taken everything imaginable of the last decade, which we will definitely share details of at the investor day. And our one remaining conclusion was that what we are witnessing in Prevail is beyond decay rates that we've witnessed in the last decade. So that was your second question. The first question was on the effect size. Well, stopping rules are based on a p-value. and they're not based in that sense on a hazard ratio. And so that is, and we're not going to reveal the p-values today, of course, but I can tell you, so it has nothing to do with hazard ratios. It has to do with actually achieving a certain p-value. And that p-value then, and by the way, the DSMB has this unique power that it's in their discretion to stop a trial. We have, I mean, they're given stopping rules. So if certain P values are met, they can stop the trial, but they can always say, okay, well, for this or that reason, we don't stop the trial. And by the way, in a previous question, it was suggested that doing the interim is in fact pushing the second outcome of the trial at the end of 27 out. And that is not true. I mean, I mean, going all the way till the end of 27 is going all the way till the end of 27. The interim is simply in the middle of that because of the data that we have seen so far, which makes Michael and I, with all of our experience in lipid lowering trials and CVOTs, optimistic that we're seeing a treatment trend.

I just want to add to what John said. We've looked at every trial in the last decade. placebo rates, decays, and so forth. And all we can say is you can look at not just lipid trials, but you can look at, you know, Select is a good example. The thing about Prevail that we want to continue to emphasize, it was designed as a higher event trial. It has a higher baseline LDL. It has a higher rate of diabetes. It has a high rate of MI and stroke to get into the trial. So You know, we're expecting a high placebo event rate, and we're seeing, again, event rates that are lower than expected, you know, based on these analyses. So, again, it's a very encouraging sign, but we have to finish the trial and see what the results are. But as we said, we don't want the study to fail the trial, and so that's the fail the drug, study to fail the drug. And the drug, we believe, is a fantastic drug. And it has a lot of benefits beyond LDL lowering. And we'll see those benefits hopefully demonstrated in the outcome of Prevail.

Your next question comes from Deepjit Chattopadhyay with Guggenheim. Please unmute your line and ask your question.

Hey, good morning. Can you hear me? Yes, Deepjit. Yeah. Thanks. Hey, good morning, and thank you for taking my question. Most of them have been addressed, so maybe I'll touch upon the recent South Korean intensive LDL-C lowering study published in the New England Journal about a month ago, and how that could be sort of a harbinger for what we could see in Prevail. And if you were to sort of strip out Lp and your traditional LDL-C reduction from the discussion, What do you think is the effect of elimination of small LDL-C particles on the overall lower event rates that you're seeing? Thank you so much.

John, do you want to take that?

Yes. So the South Korean trial published in the New England Journal of Medicine was a fantastic landmark. that shows that intensive lipid lowering started early gives a great benefit. Now, Michael and I have been proponents of that since probably the last three decades. So for us, it was not much of a surprise, but it's always good to see it in print and definitely also see it in the New England Journal of Medicine. So it tells you again that if you start early enough and you go deep enough, that you're rewarded with a fantastic MACE risk reduction. So in that sense, that was very good news. Now, in terms of the LDL particles, I'd like to highlight one thing is that Everybody acknowledges that when you're diabetic, insulin resistant or obese, the first thing that changes in your lipid profile is that you have you are getting a preponderance of small LDL particles now and a lot of them. And those particles are very heterogenic. you can easily oxidize them. And because they are smaller, it's extremely likely that they'll enter the arterial wall more easily and are attached to proteoglycans and are absorbed by macrophages and which kind of starts the whole atherogenic cascade. So nobody likes a small LDL particle. But how do you get them? Well, you need CETP for that. So CETP is biologically a must to construct these particles. So it's very, very intuitive that if you inhibit CETP activity by 98%, as we do with basically knocking out CETP activity, that it's becoming very hard to create a small particle. And that's why our drug is so efficacious against these particles. Now, with all the epidemiology of the particles being nasty on one hand, and on the other hand, the evidence that we've shown in phase three, that our drug reduces these particles by 80 to 90% or something, two and two is four, it's very likely and attractive to hypothesize that that will yield a large effect size. Now, no one has ever been able to show that in an outcome trial, of course, but I think it's reasonable as a hypothesis, and if that is true and the LP little a effect is null, then I do indeed agree with you, and Michael too, I think, That beyond LDL, actually our treatment effect in Broadway is based on the fact that obesetrape reduces small particles to a large extent. Yes.

Your next question comes from Steve Seedhouse with Kantor. Please unmute your line and ask your question.

Great. Thanks so much. A three-part question. All just clarifications, though, I think. Hope that's okay. So first, just can you quantify maybe the event rate through two years and just share how much it has changed in year two relative to year one? Second, Have you conducted any analysis of the total events sort of so beyond year two in those patients where the data is available and have a sense of how it's tracking beyond year two? And then it sounds like since you're looking at MACE3 and MACE4 that you might have blinded analysis of sort of the individual components. Curious if you can share if it's sort of proportionally less across components or if there's a particular driver of the lower than expected event rate in year two.

We have all that data. We're not going to share the actual event rates because I said one thing we want to just lock in is we are almost done with adjudicating all the events, but we want to complete that completely. There's just a few left that we want to make sure we got the exact number correctly when we have investor day in August. So we're not giving the number out, but we are looking at every component. And every component is going in the right direction, which, again, is more – it gives us, again, the belief that the drug has a great effect on reducing across the board all the outcomes. So we are seeing this predominant benefit across the board on all the events, all the different components as well as the total events. So that's all part of what we're looking at. Again, it gives us again the encouraging belief that the interim is the right thing to do.

And the trend beyond two years, Michael?

Well, that's the other thing. The further we go out, we have to keep in mind that we don't have as many adjudicated. We have a really good model for predicting which converts to adjudicated events positively, which is what you can do, but it keeps looking even better over the longer we go. That's, again, another part of the... The things that we're tracking, the events keep coming down in year two to three as well.

As a reminder, if you have joined via the webinar, please use the raised hand icon down at the bottom of your screen. When you're called on, you'll unmute your line to ask your question. And as a reminder, to allow for as many questions as possible, we ask that you please limit yourself to one question. Your next question will come from Jarwei Feng with Citigroup.

Hey, guys. Good morning. This is Jarwei on for Jeff. Thanks for taking our question. And maybe just a question on the early stop scenario. I mean, is there a scenario where p-value meets the DSMB early stop criteria? but then that still leaves hazard ratio benefit on the table that may make OB more appealing to prescribers. I know you guys have talked that alpha and statistical powering does take that into consideration, but just wondering if maybe there may be benefits even continuing the study even beyond the interim analysis if the p-value were to hit. And then a second question on the placebo rate and event rate decay is, I know you guys take a look at everything holistically, PCSK9s and SGLT2s and GLP1s, but specifically for CETP studies, have those historically shown a precedence in event rate deceleration? Thanks.

John, do you want to take that?

I'll again start, sorry for that, with the last question. The placebo arms in CTP inhibitor trials are just like every other placebo arm, and they have also shown historically some decay. Yes. Now, of course, it's... Going back to the first one, the Pfizer one, actually is very long ago, but Reveal, the trial that actually showed for the first time that CETP inhibition with anacetopib reduced MACE statistically significantly, is being used by us. This was a 30,000 patient trial. I'll not give any numbers on event rates, but The upper tertile of that trial, by definition, is a third of 30,000. That's 10,000 patients. That one third is quite similar in numbers to Prevail. So we are using that database very frequently to study all sorts of aspects of this. And also there is a, in the placebo arm, there also is some decay. But again, when you see it holistically, if all these trials together are reduction of event rates or our slowing of event rates is different than what we've seen in a meta-analysis of these trials.

Go ahead, John.

Go ahead, Michael. I just forgot the first part of the question.

So in Reveal is an important study to look at. We keep referring to it because that's why we're doing Prevail. Prevail pretty much mimics the upper tertile of Reveal. If you do actually look at the that upper tertile separately, and there was a 17% relative risk reduction with a 23 milligram per deciliter drop in non-HDL. Our non-HDL lowering is going to be substantially more than that, you know, based on the Broadway data. And then that upper tertile, which we track, you know, we track that upper tertile event rates that at the end of the four-year mark, and we'll be closer to the three-and-a-half-year mark with... with our interim analysis timelines, they had a significant difference already at that point in that upper tertile for their MACE4 endpoint. So anyway, that's also encouraging. So we look at that study as the one CTU inhibitor where we believe that we have the most comparability to

Yes, absolutely. I do remember the first part of the question. So the benefit of a lipid lowering drug, and for that you can go back to the CTT meta-analysis paper where they analyzed the benefit of year one, year two, year three, year four. The vast majority of benefit is already achieved at the end of the second year. That's where we are right now. When we do the interim, we'll have a median follow-up of something like three and a half years. So it is not true that the curves go two years, three years, that they go bigger and bigger and bigger. So if the interim hits and actually the trial is stopped, it is very unlikely that it will give a big additional effect size over a year. You know, it will have more power. Because the numbers are much bigger, so we'll have more power to show a lower hazard ratio at that time. But we feel that, and that's one of the reasons why we feel it's justified to do the intrim right now, because we feel that we are pretty close to the max effect at that specific intrim time.

Yeah, and to reveal as well, there's about 1,000 events in that upper tertile, and we'll be over that at the time of the interim. I think we want to just keep emphasizing why we're doing the interim, but we're not jeopardizing the overall study completion as well. So, again, we feel it's a win-win for the company and for the drug and for patients and for Obocetrapib. Yep.

Your next question comes from Yanon Zhu with Wells Fargo. You may now unmute your line and ask your question.

Great. Thanks for taking the question and thanks for the update. The South Korean EZ-PAVE trial was touched upon a little earlier. I thought during that presentation at ACC, the presenter mentioned there weren't enough events in that study. And I think the New England Journal paper also stated as such. Have you had the chance to look at that study and understand whether, and of course that study had a 33% risk reduction. for the more aggressive targeting versus conventional targeting. Have you had the chance to look at whether that trial had a fewer event than expected due to the more aggressive targeting arm? or is it because both arms kind of underperformed or had less event than expectation? My second part of the question is, you talked a lot about the placebo arm in prior trial and how to think about degradation. I was wondering in the treatment in active arms of prior trials, do you see typically that the effect come on more after the second year, i.e. not a linear effect from year one throughout, but rather have some kind of acceleration after second year? Thank you.

So it's always important that trials are not seen in isolation. And again, I'll start with your last question. So in the CTT meta-analysis, there were 170,000 patients, and I don't remember how many trials, but many trials. You know that for 38 milligram per deciliter, LDL see absolute difference. There's a 22.3% reduction in MACE. Now, When do you get there, that 22.3%? In year one, you actually are about half. So about 12%. In year two, you're getting very close to 20%. And in year three, you're basically at the 22%. So that... There is no. So these are the numbers. So you have to get beyond year one. That's the first thing that you can learn from these meta analysis. But once you have reached the end of year two, you pretty well know what the effect size is for a given LDL reduction. So that's one thing. The second thing is that you alluded to the South Korean trial again. It's not the only trial of more intense towards lower intense therapy. I was on the executive committee of the TNT trial with atorvastatin 80 versus atorvastatin 10 again. This was like decades ago, so we've had a long history of this, and there might have been fewer events, and therefore the point estimate and the confidence intervals might not be overwhelming, but we cannot look at trials where there is no placebo arm for a decay rate. We need a placebo arm for a decay rate, and the whole idea is if you look at blinded data, if you look at blinded data and actually you want to understand what's happening with a curve the only thing you need to know is the placebo event rate because if you know the placebo event rate you'll know by definition what the effect size of the drug is and so therefore in order to understand this you have to compare to placebo event rates preferably most recently, but I think a window of about a decade is a fantastic window. So these more towards less intense therapies do not help us. They don't help us understand that. It is trials like Reveal and Fourier and Odyssey and Vasalius and Clear Outcomes and Sol and Select. And all of these trials really help us because they have a placebo arm. And we can, because we know exactly what our baseline characteristics are in Prevail, very similar to Broadway. We know what the expected event rate is, and we can build in the decay and then do our estimates. But looking at trials with two treatment arms is not going to help us understand this.

Yeah. And the event rates you mentioned, the event rates were really low. I mean, we're talking about event rates of 95 versus 141, which we're well, well over that. Now we're in the thousand plus event rates, just so you know. I mean, so it's just getting much more well-powered compared to what they saw in that New England Journal study, which was great. I mean, we all believe. Great study. Yeah. The lower is better, but that was a nice benefit that was achieved. Again, it supports, again, the whole hypothesis that we're trying to develop with Obacetrapib is the lower the better, and not just LDL, but other parameters as well that we hope to achieve with Obacetrapib.

Your next question comes from Sebastian Vanderskoot with Kempin. Please unmute your line and ask your question.

Hi, team. Very exciting news. Congratulations. I think that you pretty much indicated you expect that you will have enough power to hit that sick on every single maze component. I'm just wondering, when you are looking at these blinded curves for those components, is there anything that stands out to you that is differentiated from other components? cardiovascular drugs. And can you maybe also speak to the importance of these individual MACE components for the eventual label in the marketing of Obesetabit? Thank you.

Let me say, we haven't disclosed individual components, but we're saying they're all in the right direction. That's the only thing we're saying, that we see a consistent benefit across all the components, which is great. However, I want to point out that the FDA has harmonized their labeling now, where you don't have to hit each individual component now to have that in your label. That was a change that the FDA made roughly a year ago. As long as you have those composite events in your, those events in your composite, you get that in your label, even if the additional components are not selectively statistically significant in their own right. So that's, again, that's why we added ischemic stroke to the four-point MACE, because we can say ischemic stroke benefit, which again, tends to always consistent with other LDL lowering components, But right now, with the FDA's new guidance, we don't have to have each component individually statistically significant. That's another reason why the interim, we believe, is a good idea, that the FDA has given us that new way of how they do the labeling. So I think we're at the top of the hour. Is there one last question that we could – one more question we'll take?

Yes, our final – Our final question will come from Kripa Devakonda. You may now unmute yourself and ask your question.

Hey, guys. Thank you so much for taking my question, and thanks for all the color today on the call. A lot of my questions have been answered, but I'll ask a question regarding some data that you presented at ACC where you showed slower EGFR decline and nominally pure renal events. I was wondering if you can help put this in context for us. How meaningful is the difference that you saw in EGFR and the lower renal event risk? And how does this impact the broader profile of OB from a competitive standpoint? Thank you.

Can I answer that, Michael? Yes. So this is, please realize that this is only one year So the phase three trials, the pivotal registration trials by definition are only 12 months. And so any improvement in EGFR is very clinically relevant because normally you would take a drug like this for 25 years. And we all know that in patients with ASCVD, you see a gradual decline of renal function over time. And the fact that already within this relatively short space of a year, you see less renal events and less renal decline of EGFR is very clinically relevant. And actually, I'm not a nephrologist. I'm a professor of medicine, and Michael is a professor of cardiology. But the nephrologist that we have consulted to actually write this up, to make this into a paper, we're very excited about it. So it's very clinically relevant. In terms of the gestalt, very likely this is also the consequence of raising HDL cholesterol and raising small HDL particles. The same biology that very likely drives less new onset type 2 diabetes and might even drive the Alzheimer biomarker studies. And so we think that that gives us a very nice competitive edge in the marketplace because there is no other drug that raises HDL levels or HDL function like Obesetra PIP.

Okay.

We have reached the end.

Okay, yeah, go ahead. Thank you very much. We will hopefully, we'll be working, obviously seeing a lot of you in upcoming meetings, and we look forward to providing more information, especially on our August 5th Investor Day coming up. So again, everyone, really appreciate your listening to us, and we will continue to update you when more data is available.

Thank you. That concludes today's call. You may now disconnect.