NewAmsterdam Pharma Company N.V. ($NAMS)

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 NewAmsterdam PREVAIL Update Call. [Operator Instructions] At this time, I would like to turn the call over to Matthew Philippe, 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 Somaiya, 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 2 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 PREVAIL 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 NewAmsterdam. 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 obicetrapib, including the latest time lines 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 rate in PREVAIL is tracking in line with what we saw in BROADWAY, which John will discuss in more detail shortly. This is consistent with the intent and design of this trial. Importantly, the year 1 to year 2 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 the 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 MACE-4 to include total coronary rather than urgent revascularization and an expected mean 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 MACE-3 and MACE-4, we will be well powered to detect the difference at the interim. These data remain preliminary as we continue to adjudicate -- complete adjudication of year 2 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 2-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 MACE-4 endpoint that we could attribute to multiple factors, including LDL particles, lipoprotein(a), and there is some room for potentially other factors such as less new onset type 2 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 6 months and then separate. To further corroborate this, on the right hand on the slide, we show a landmark analysis that starts at the 6-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 III 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 2 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 an almost perfect comparator to PREVAIL and the fact that we already saw a 21% reduction of the 4-point MACE in BROADWAY, makes all of this, of course, fairly 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 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 6 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 obicetrapib 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 1-year mark to the 2-year mark. Based on the trends we observed in BROADWAY and the slowdown in events from year 1 to year 2, 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 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 the 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 1 to year 2 in the blinded PREVAIL data, we are optimistic that this is being driven by a treatment effect. With that, I would like to open the call for questions. Thank you.

[Operator Instructions] Your first question comes from the line of Yasmeen with Piper Sandler.

Can you hear me?

Yes, Yas, we can hear you.

Okay. Sorry about that. This is Shannon on for Yasmeen Rahimi. I had a little bit of trouble with the unmute. But just two questions for us. About the interim analysis, could you speak a little bit more about why 4Q '26 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 the penalty there? And then just about pelacarsen's HORIZON study coming out in early half '26, could you talk a little bit more about potential read-through to PREVAIL and the expectations there?

Sure. I'll start. I'll turn it over to John a little bit also. But -- so 2026, for those that are familiar with the trial design, we had a 2.5-year minimum follow-up, and that's the timing of that. So that's part one. But also, we'll have enough events at that time, especially 4-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 provide an interim 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 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 that 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 -- at 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 recent LDL-lowering trial. So we want to make sure the study overall is still very well powered to achieve those -- 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 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 it over to John to answer that question because he's very involved with -- was involved with that study prior to his role in NewAmsterdam. And he can give you a little bit of insights from what we understand about the biology of Lp(a) as well to address that second part of your question. So John, I'll turn it over to you.

Yasmeen, this is John. As you know, in our Phase III program of obicetrapib, we have shown that 10 milligrams once a day actually lowers lipoprotein(a) by 45% to 50% in the range between 50 and 150 nanomole per liter, which, by the way, was just today accepted as a paper in the European Heart Journal. I just got the e-mail 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(a) and reduction of ASCVD events, we can use those data to make the translation what that would mean for obicetrapib 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. I think that the epidemiology, the genetics and the Mendelian randomization is extremely strong for Lp(a) as a risk factor for heart disease, but it is the first trial. It is not the most potent Lp(a) lowering drug out there, and you never 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 obicetrapib is very clear.

Let me just add one other comment to that because we all hope Lp(a) lowering with pelacarsen is successful. 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 statistical power, the p-value for approval or there are side effects, whatever that might -- we know the platform itself, you do get certain side effects, skin reactions and so forth. That will make the therapy either 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 Lp(a) lowering in general. But that could put us as one of the first Lp(a) drugs, although we're not indicated for that, it could be one of the first oral therapies to lower Lp(a) in that 50 to 150 range by approximately 50%. So we feel that a study that may not -- is positive, great, that's fantastic for everybody. It has a relative risk reduction, 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.

Your next question comes from the line of Tyler Van Buren with TD Cowen.

Hello, can you hear me?

Yes, Tyler. Yes, we can.

I'll do my best to stick to one question here. So regarding the year 1 to 2 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 as to trials in the past and standard of care potentially might have changed since then?

Yes. 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 we could -- you could adjust for their LDL baselines, their percent diabetes, their percent with post-MI or stroke and so forth -- and age and so forth. And also -- we also, of course, adjusted for the add-on to GLP-1s and SGLT2s, which, by the way, we've had a very little add-ons in our trial. We keep making that point. I know people worry about that, but we're tracking that PCSK9s 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 FOURIER, CLEAR Outcomes, the VESALIUS trial. The VESALIUS isn't really -- a little different because it's a primary prevention trial, SOUL, SELECT, all these other trials that have been done recently, they just completed. You can model very well what the placebo event rates will be. And so we've done that, and we hope to share more at our Investor Day in August. But also, we, of course, have BROADWAY, BROADWAY being the mini-PREVAIL, it gives us a very good prediction of placebo rates in PREVAIL. And so when you do that and you see the event rates that were -- blinded event rates that we're tracking in PREVAIL, we're very encouraged by that. And so that gives us the belief that an interim is the right thing to do to maybe get the 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, FOURIER, ODYSSEY OUTCOMES, CLEAR Outcomes, even VESALIUS had 19% in their 4-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 that a CETP inhibitor trial. We don't want to, in any way, jeopardize those chances. So we think an interim is the best way to go because we're so encouraged by the data. But yes, 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 U.S. 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 3, 4, 5 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. As you know the lines in that slide are completely on top of each other for the first 6 months. And so we, 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 Roanna Ruiz with Leerink.

This is Michael Ahn on for Roanna Ruiz at Leerink Partners. So when you report the interim results in 1Q '27 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 at interim itself be informative for the final readout?

So if the interim doesn't stop the trial, we won't know anything other than that. The study will continue. And the DSMB, they do have stopping rules for the trial that 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 powering the study down to the typical 15% hazard ratio that I've 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? That's -- we're not going to know anything more than that.

The related question, Michael, was a follow-up, 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 of MACE-4, 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 that the trial succeeds, and we have 2 point -- 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 minimal statistical penalty for doing the interim analysis, and that also informed our decision.

Your next question comes from Dennis Ding with Jefferies.

So you 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?

Thanks, Dennis. So yes, of course, this was a decision. I think what was -- again, the driving factors were -- the statistical penalty is minimal. So that's -- so there's really no major risk there for the overall trial result. And secondly, we would not be doing this unless we saw something really encouraging already. That's the key things that 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 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 entry to the market roughly 1 year earlier 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 obicetrapib. Regarding the FDA. We are working closely with the FDA on how to think about the interim, and how to apply that to our filing time lines. But that discussions are in play, and we'll get more details to you after August 4 -- August 5 Investor Day. We'll provide more details on that, but those discussions are presently ongoing.

Importantly, we can say that we also obviously submitted these trial amendments to IRBs, which several have been cleared, and those changes are now in place.

Your next question comes from James Condulis with Stifel.

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 like 20% to 21% MACE? Or what happens if you show like a 15% MACE benefit in this interim? And then two, just a quick kind of clarification on these other trials. Is there like a couple -- 1 or 2 key trials that you think are good analogs for declining event rates that were an encouraging sign, or do you think kind of all of these trials like all of the PCSK9, et cetera, all sort of follow this trend that have had positive outcomes?

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 the bempedoic acid trial and look at the placebo rates year 1, year 2, year 3 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, oh yes, on the -- yes, the effect size. Well, stopping rules are based on a p-value, and they are 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 if -- 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, going all the way until the end of '27 is going all the way until 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 on placebo rates, decays and so forth. And all we can say is you can look at not just lipid trials, but you look at -- 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's a higher rate of diabetes, higher rate of -- it has a high rate of MI and stroke to get into the trial. So with expecting a high placebo event rate, and we're seeing, again, event rates that are lower than expected 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 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 Debjit Chattopadhyay with Guggenheim.

Can you hear me?

Yes, we can. Yes.

Thanks 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 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(a) 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?

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 atherogenic. You can easily oxidize them. And because they're 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 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 III that our drug reduces these particles by 80% to 90% or something. 2 and 2 is 4, 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(a) effect is nil, 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 obicetrapib reduces small particles to a large extent, yes.

Your next question comes from Steve Seedhouse with Cantor.

A three-part question, all just clarifications, though, I think, I hope that's okay. So first, just can you quantify maybe the event rate through 2 years and just share how much it has changed in year 2 relative to year 1? Second, have you conducted any analysis of the total events, so beyond year 2 in those patients where the data is available and have a sense of how it's tracking beyond year 2. And then it sounds like since you're looking at MACE-3 and MACE-4 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 2?

We have all those -- 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 2 years, Michael, I think.

The trend here keeps -- 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 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 things that we're tracking. The events keep coming down in year 2 to 3 as well.

[Operator Instructions] Your next question will come from Jarwei Fang with Citigroup.

This is Jarwei on for Geoff. 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 leaves hazard ratio benefit on the table that may make obi more appealing 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 benefit to 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. I know you guys take a look at everything holistically, PCSK9s and SGLT2s and GLP-1s. But specifically for CETP studies, have those historically shown a presence in event rate deceleration?

John, do you want to take that?

Yes. I'll again start, sorry for that, with the last question. The placebo arms in CETP inhibitor trials are just like every other placebo arm, and they have also shown historically some decay, yes. Now of course, we -- 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 anacetrapib 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 1/3 of 30,000, that's 10,000 patients. That 1/3 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 of all these trials together, our reduction of event rates or our slowing of event rates is different than what we've seen in the meta-analysis of these trials. And then...

Yes, go ahead. Go ahead, John.

No, no. Go ahead, Michael. I just forgot the first part of the question.

So 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 which showed a statistically significant. If you do actually look at that upper tertile separately, 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 based on the BROADWAY data. And then that upper tertile, which we track, we track that upper tertile event rates that -- at the end of the 4-year mark, and we'll be closer to the 3.5-year mark with our interim analysis time lines. They had a significant difference already at that point in that upper tertile for the MACE -- their MACE score endpoint. So anyway, that's also encouraging. So we look at that study as the one C2 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 1, year 2, year 3, year 4. The vast majority of benefit is already achieved at the end of the second year. That's where we are right now. But when we do the interim, we will have a median follow-up of like something like 3.5 years. So it is not true that the curves go 2 years, 3 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, it will be -- we 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 interim right now because we feel that we are pretty close to the max effect at that specific interim time.

Yes. This also give -- in 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 that why we're doing the interim, but we're not jeopardizing the overall study completion as well. So it's again, we feel it's a win-win for the company and for the drug and for patients and for obicetrapib.

Your next question comes from Yanan Zhu with Wells Fargo.

The South Korean Ez-PAVE trial was touched upon a little earlier. I thought during that presentation at ACC, the presenter mentioned that there weren't enough events in that study. And I think the New England Journal paper also stated as such. Have you had a 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 a chance to look at whether that trial had a fewer events than expected due to the more aggressive targeting arm? Or is it because both arms kind of underperformed or had less events than expectation? My second part of the question is you talked a lot about the placebo arm in prior trials, 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?

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-C absolute difference, there's a 22.3% reduction in MACE. Now when do you get there, that 22.3%? In year 1, you actually are about half, so about 12%. In year 2, you're getting very close to 20%. And in year 3, you're basically at the 22%. So that there is no -- so these are the numbers. So you have to get beyond year 1. That's the first thing that you can learn from these meta-analysis. But once you have reached the end of year 2, 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 the 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 VESALIUS and CLEAR Outcomes and SOUL 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.

Yes. 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 over that. Now we're in the 1,000-plus event rates, just so you know, I mean, so it's again 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, yes.

All right. 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 obicetrapib is the lower, the better and not just LDL but other parameters as well that we hope to achieve with obicetrapib.

Your next question comes from Sebastiaan van der Schoot with Kempen.

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

Let me say we're not -- we haven't disclosed individual components. So 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 real components are not selectively [ statistically ] significant in their own right. So that's -- again, that's why we added ischemic stroke to the 4-point MACE because we could 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...

Our final question will come from Kripa Devarakonda.

A lot of my questions have been answered. I'll ask a question regarding some data that you presented at ACC, where you showed slower eGFR decline and nominally fewer 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 obi from a competitive standpoint?

John?

Did I answer that, Michael? Yes.

Yes, please. Please, John.

So this is -- please realize that this is only 1 year. So the Phase III 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 decline of eGFR is very clinically relevant. And that -- and actually, the -- I'm not a nephrologist. I'm a professor of medicine, and Michael is a professor of cardiology. But the nephrologists that we have consulted to actually write this up to make it 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 obicetrapib.

We have reached the end.

Okay. Yes. 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 5 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.

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