NewAmsterdam Pharma Company Aktie

All right. Good morning, everybody. Thank you for joining us. today for our Annual Investor Day, I'm pleased to have Michael Davidson, our CEO; John Kastelein, our Chief Scientific Officer; and BJ Jones, our Chief Commercial Officer, here with us today along with many members of our team. Ian Somaiya will also be available for questions afterwards for the presentation.

Before we get started, the fun part, we will be making forward-looking statements today. advise everyone to please read our forward-looking statement page, either here in the room or also available online at this time. As we mentioned today, we'll have Michael being going through a general corporate update and introduction.

We'll have John presenting the science, then we'll go back to Michael for an update on PREVAIL as well as some of the updates on AD, and then BJ will be going through commercial.

At this time, I'd like to have Michael come up join us. Michael?

Thank you, Matt, and thanks, everyone, for being here. We're very excited to share with you our science and corporate update. For us, this is our third Investor Day Science Day. And for John and I, it's one of our favorite days of the year. We get a chance to talk to you about what we're doing at New Amsterdam, all our achievements.

Of course, for us, the most exciting thing about the company is developing new science, helping patients. And so we really want to share with you all our insights and where we are and look forward to your comments and questions afterwards. So we have a new mission statement that I'd like to review with you. Our mission is to hold a new standard of care for people living with cardiometabolic disease by challenging connections with courage, transferring deep biologic insights into meaningful patient impact and delivering with rigor, precision and purpose. This is how Amsterdam built to go beyond. And so we have thought about all this each word and what it means for us. And of course, we always believe in our other model, which is expect more.

We believe obicetrapib is the type of drug that you can expect more when it comes to delivering better patient outcomes and improvements across multiple disease modalities. I'd like to start, as all of you know, I still see patients 4 days a month at the University of Chicago, I run the lipid clinic. This is a patient of mine, Frank, who's been with me for almost 40 years. And I bring this up because when Frank came to see me for the first time at age 36, I had super high cholesterol LDL. He had diabetes, very bad family history. I just saw him in the clinic a week ago, and he looks great, 76. We lost a lot of weight, his diabetes is pretty much gone, and he's got a very low LDL and no evidence of clinical cardiovascular disease.

And so this to me is the inspiration that drives me, and I think in many ways, helps me encourage all our great advancements we have in Amsterdam and motivates us to make sure that we can deliver better medicines to make a difference in people's lives. So let's talk about the new Amsterdam value proposition. We have good clinical expertise. That's been our background. John and I have been in this field for 40-plus years. And I think as you'll hope to see in our discussion today, we designed our clinical development program to maximize success, especially PREVAIL.

A lot of learnings have gone into how we went about designing PREVAIL and the modifications we made in the PREVAIL trial. Most important of all is the success of PREVAIL and how that will build value for both in Amsterdam and for patients. Obicetrapib, of course, we're blessed with a great drug. This drug not only lowers LDL, but has a multiple effects on many different biomarkers of cardiovascular risk. And of course, we're very excited about the new data on Alzheimer's prevention that we believe is going to be a hallmark of this drug going forward.

Now the unmet need is something that we focus on all the time. I said, I still see patients. And if you read JAMA this week, they have a great article about the global impact of high LDL and 6 million lives lost, 90 million morbidity events every year due to high LDL. And if you look at the maps, the U.S. population, the LDL levels have basically flatlined. They have not changed in almost more than 20 years. And the mortality rates haven't changed. If not, they're going up. And so we're all excited about all these new therapies, GLP-1s and so forth.

But we all know that based on the data, heart attack rates are same or climbing, stent PCI rates are climbing. So heart disease continues to be the leading cause of death and LDL levels that are elevated is the main contributor to that. We have been really focusing on building out our team, and I'm excited to have BJ share with you the great additions to the team that we've had in the last few months, remarkable people, some of them here today, but we appreciate if you have a chance to meet them and hear about their backgrounds because it is a phenomenal team that we're developing across the company.

Now KOL support continues to build. We've had MSLs in the field for more than 2 years now. And the feedback we're getting from the KOL community is really very encouraging and inspires us to keep going and to prove the benefits of obicetrapib across the disease spectrum. And our CMC team, we don't talk about this too often, but it's a phenomenal team. They just won the Green Chemistry Challenge Award, which is like the Nobel Prize of manufacturing and very proud of that team and all they've accomplished.

But I think the most important thing for the value creation is develop a very robust supply chain for obicetrapib in a fixed-dose combination and preparing us for launch in Europe and across the world. And the final point, again, is the -- is where we are moving forward as a company, and we're really excited to share with you where we're going today and into the next few months.

So the accomplishments, just to highlight for you the key things across all our data with Broadway and Brooklyn and Tandem, building out our team and doubling in size. We're now more than 100 people and opening up a new office outside of Philadelphia, along with our office in Miami and Amsterdam. And of course, we've been blessed with securing a large amount of financing on our cash balance of $678 million, which gives us plenty of cash to launch this drug when the time comes.

So let me give you a few important kind of key takeaways from the market itself. Again, I have this insight in my own practice of what's going on. I think we can say that the market is growing. You heard today even from Amgen about the growth, 37% globally, 50% growth in Repatha in the last year. So this is an incredible growth in the lipid market. The guidelines have been revised recently to bring -- go back to goals, 55 LDL for the very high-risk patients. That's a huge number of patients. They're going to be added to the number of patients that need to be treated to get to the adequate levels to reduce cardiovascular risk.

And the other important attributes are the FDA guidelines -- sorry, the FDA labeling that they're allowing now for lipid drugs is getting broader and payers are responding to that, and we've seen a much more broader access for all the LDL-lowering therapies. So for us, this represents a market, and BJ will go into more detail later. This is a market that's growing, growing robustly. The guidelines is changing. It still hasn't reached the impact it's going to have. New entries in the market is going to grow the market even more.

So we feel we're really in a great position with obicetrapib to really do very well, and I'm very confident that the drug will launch exceptionally well across the world. And we're excited about our first regulatory recognition from the CHMP have recommended for approval by the EMA. For John and I, in particular, just focus on John. We've been working on CTP inhibitors for 25 years and to have the first one approved by a major regulatory body, we think, is a huge milestone. And we're very proud of this accomplishment, working with our Menarini partners.

And therefore, we're all set to potentially get approval in Europe in the very near future. So a very exciting time for us with this regulatory recognition. So now for the science update, where we're going. And like I said, this is our favorite day of the year for us to get in front of all of you and talk about what Amsterdam is developing around obacitrapib as well as what other things that we're considering when it comes to how to differentiate this therapy from all other LDL-lowering treatments.

I'd now like to turn it over to John to go through that science. Thanks, everybody. I'll be back.

Yes. So I've really done my best to add new science into my lecture because I do know we are not the only company that you have to listen to. And so the last thing I want is that everybody is bored to death and then leaves and then thinks, oh, the coffee was nice, but that was about it. So I've done my best, and I would like you to leave this room a little later with our teaching that CETP is so incredibly central to human biology that it does way more if you inhibit it than just simply lowering cholesterol.

And I think that is by far the most important lesson. And we have a number of presentations coming up at the ESC at the end of August at the American Heart. We have a paper, 2 or 3 papers about to come out with data that speaks to the additional effects of obicetrapib, not just simply lowering cholesterol. It's not a cholesterol lowering drug on its own, and that's almost impossible because as you know, we've told many times before, obicetrapib knocks this target out by 98.3%. So basically, what you do is you create a rabbit from a human, if you kind of think about it because, in fact, most rodents don't have CETP. We have CETP, and it's a gene that we shouldn't have had. It's an evolutionary mistake for us. We don't need CDP at all. And so inhibiting it is actually a very, very good idea.

The only problem was is that in the last 25 years, as Michael was referring to, either the drugs were useless or the trials were useless. So we have finally arrived at a point where Michael and I and the entire team have designed the trials, and we have a compound that can do what we've always wanted to do. And so this kind of rainbow you've seen before, but it kind of really highlights all the additional effects that no other lipid-lowering drug has. You go from lowering lipoprotein(a), and I do understand we need Horizon to completely understand what that means.

We'll get it at the American Heart Meeting. Then there's the whole particle stuff, but the biology, and I'll show you that is so compatible with CTP driving small particles. And if you knock CTP out, there are no more particles to drive to, then there's the LDL, non-HDL, small dense LDL cholesterol, oxidized LDL. So on the atherogenic lipoprotein part, we have influence on almost every biomarker that we can measure. But that's not everything. And what's getting more and more important, it's the HDL part of things. So the HDL part of things without any doubt, is driving what we see in Alzheimer's, it's driving what we see in renal disease and is driving what we see in the diabetes part of things.

And I'm going to show you today 2 analysis that it's very likely also contributing to the MACE outcomes -- and in fact, the godfather of ApoB, Allen Sneiderman, just 2 days ago, published a paper from the U.K. Biobank, 0.5 million people that shows that HDL changes the relationship between ApoB and MACE. So the higher your HDL, the less ApoB can be bad for you. And that is a totally novel insight, and we have found exactly the same, and I'm going to present that at the European Society of Cardiology. So it's no longer only Lp(a) particles, diabetes, but it's now also HDL that's becoming biologically important and of course, also clinically important for us at New Amsterdam Pharma.

So -- the question, of course, always is when you start -- actually, it's interesting because it is a new target currently because there is no marketed CETP inhibitor out there. So what you would normally do if you develop a new PCSK9 inhibitor, for example, you go back into history and say, what did other PCSK9 show? And so I think that it's very, very learning to see what other CETP inhibitors actually showed in terms of changes in MACE.

Now of course, there are many, but there was only one reasonable one, which is anacetrapib and Merck. And for that, I would like you to go back and let these numbers sink in. So the last CETP inhibitor trial before us was REVEAL. REVEAL was anacetrapib, a mirv drug, 100 milligram, inhibited CTP by 75% to 80%, not 98%, 75% to -- it lowered LDL by 17%. But look at the number. This was the largest ever CVOT on the planet, 30,449 patients for 4 years, in fact.

This year, Oxford is doing the 10-year follow-up of this trial. The 7.5-year follow-up showed that, that 17% was actually, if you look at over the long run, conferring a much larger benefit than everybody thought. So this is a much weaker CETP inhibitor and 1/3 of that trial, 1/3 of the 30,000 is 10,000 by definition, just as big as PREVAIL. So we have a trial here that's 3x bigger than PREVAIL. And so what we can do is we can actually look at that trial and say, let's take the patients that are basically similar to PREVAIL and what did a weaker CETP inhibitor with a lower LDL reduction did because in this trial, it did 9%.

And that 9% is actually better than what was expected. If you calculate that 17% reduction and put it on the CTT MET regression line, it should be 6%. So that looks like a little difference. But in terms of percent, it is not a little difference. So actually, already in REVEAL, there was this kind of inkling that CTP inhibitors do better than just based on the CTT natural regression line. And so Oxford, we have a very good relation with Oxford, and I think they are still the best trial people in the whole world. And this is a very interesting graph because this is tiles. So every dot is 10,000 patients.

And if you look at baseline LDL divided in turtiles, non-HDL, ApoB and you look in the highest tertile, which has a significant overlap with PREVI, you see it's no longer a 9% reduction. But in fact, for non-HDL, it's 17%. For LDL, it's 13% and for ApoB, it's 14%. So it immediately tells you that if your baseline LDL is higher, PREVAIL is almost 100, the baseline in REVEAL was 60. So if you up the baseline and then if you up the LDL lowering, we don't lower LDL by 17%, we lower it by much more than 17% that you get much better MACE reduction. So for us, this is the best kind of example from the past of where our trial is going to.

So in REVEAL, modest CTP and LDL reduction in 10,000 patients with a baseline non-HDL in the range of PREVAIL delivered a 17% reduction in MACE. So then the question becomes, if we've seen that with anacetrapib, what have we observed with ApoB and the FDC compared to anacetrapib because these data are recent, we can simply compare it. And in order to get an honest comparison, we did exactly what Merck and especially AstraZeneca did is we ran an ideal analysis. And this is we do pharmacokinetics in all of our trials. And people that have a level of obicetrapib of less than 100 nanogram per ml, only 0.3%, by the way, so a tiny group, they simply didn't take their drug.

So we do an on-treatment analysis of BROADWAY, Brooklyn and Tandem and what kind of numbers are coming out of there, where this we will present at the European Society of Cardiology. In fact, LDL lowering at week 4 is 43.5 and at week 12, it's 41.1.

So our LDL lowering, excluding patients that simply didn't take the drug at all from the beginning is over 40%. But maybe even more intriguing, look at the HDL increase in those people. That is 140%. So this is BROOKLYN and BROADWAY. What about our fixed-dose combination? And the numbers are truly completely PCSK9like, 63% for 4 weeks, 61% for 12 weeks, and you see exactly the same kind of HDL increases. So this is the efficacy of our drug going into PREVAIL when you do an on-treatment analysis like AstraZeneca did for their PCSK9 in JAK and Merck did for their Phase III program with leaving out people that they didn't like on the basis of ultrasentific, blah, blah, blah, et cera, et cetera.

So this is -- those are data of really patients taking our drug. So what we see when you look at these numbers is that Oi observed -- was observed to lower LDL more than twice anacetrapib. And remember what I showed you, baseline about the same as PREVAIL, LDL lowering only 17% and then the return was a 17% reduction in MACE. Our drug is twice as good as that. I'm not saying we're getting twice the MACE reduction, but it's definitely going to be better than 17%. So this is a trial evidence. This is an example of let's take a large trial that's very similar to our own trial, what did it achieve in the past? Is there any -- now is there any additional evidence for CTP as a good target for reduction? This paper is about to come out in circulation. And I'm very proud of this. I'm only showing you one curve.

So what we did here with a number of different groups from Swedish universities is we did whole genome sequencing in 0.5 million people in the U.K. Biobank. So everybody in the UK Biobank has his entire genome sequenced, and these are people that had a real mutation in CETP. So they lost one allele. It was a loss of function, completely no CTP. That means, by definition, if you have one allele gone, you still have one remaining. So your CTP is 50% less. So that would be similar to a CETP inhibitor, a very modest one that inhibits CTP by 50%, we follow these people for a very long time.

Look at the red actually hazard ratio for any atherosclerotic event. It's all a bit small. I realize that, but the hazard ratio is 0.65. And this is with a 95% confidence interval that is as tight as anything. I'm not allowed to use the Dutch kind of thing for that. It's 0.65. So that is bizarre. How is it possible? How is it possible that a hazard ratio for events is so large in people that have only a 50% reduction in CDP. And the hypothesis for that is that besides lipoprotein(a) and small LDL, would the HDL difference make a dent -- because think about this, in REVEAL, the HDL difference was 100%. Our drug raises HDL cholesterol by 140%. Is it likely that, that doesn't do anything at all?

And for that, we have to just take a look at the real genetics because if you look at real genetics, you have real people with real examples. So when did we discover that humans with lower CTP did actually better than the rest of us. And for that, -- this is a New York Times abituary. This is Louise Levi. She was part of the Jewish Asskanazi Longevity project. This was a project where the investigators looked for people that were able to play bridge when there were 110 or solve a puzzle or read the Financial Times and be able to report it again. So these were people that had all their intellectual faculties way beyond 100 super centenarians. Then they took DNA, and they looked at mutations that were more prevalent in those people than in you and me.

And the first thing they immediately noted is that these people had 3.6x more mutations in CETP. So they had lower CETP than you and me. This is an old study, but it was definitely the first that indicated that if you want to get old, you'd better have a low CETP activity. That was the first. The second very interesting observation was Japanese physicians, where do we find people that have no CTP at all because Louis Levi had about a 30% less CETP. Are there any people that have no CETP? Yes, and they're all in the Far East. I've tried my entire career in Amsterdam to find the family. And I found one, and there was a Japanese family that moved to Amsterdam for financial reasons.

They work in the financial district. I've never found a Dutch woman or a Dutch man with low -- with a mutation in CTP. And what's so highly intriguing and totally irrelevant for this discussion is that it's in areas where there's endemic skistosomasis.

So low CETP protects against a parasite, immediately telling you that CETP is much more than just lowering cholesterol. It is a central biological molecule that has much more. Now of course, being protected against parasites is not that interesting for our discussion today. But what do they -- I mean, do they have other properties? And this is extremely interesting. So you have to really remember this slide. So exceptional longevity. They actually get older than the rest of Japan. They have low risk for ASCVD. They also have low risk for Alzheimer's disease. That was one of the first observations that made us after Louis' Levi, think about Alzheimer's. They also have lower risk of AMD.

Andy, one of our workers in the Department of BJ, in fact, went to Japan, talked to the Japanese investigators. We recalled these people, pushed them through an ophthalmology research, looked in their eyes, we have never ever found someone with AMD.

And then the last thing, just about to be published, there's a lower risk of sepsis mortality if you have no or low CTP. So the biology is -- I mean, all of it is good. You don't want CETP. CTP is something that you actually don't need. But then let me just dwell for 1 second on the actual lipid profile. Look at the left-hand corner, left-hand corner here. They have a 100% increase in HDL, 40% decrease in LDL and FOB, 40% decrease in Lp(a) and no small LDL particles. It's like a frigging mirror of what our drug does. And that is so interesting, so you actually can watch in the biology of human beings and people that have no CETP naturally and see that a drug that lowers CTP by 98.3% recreates the exact profile.

Now I've talked enough about LDL, ApoB and Lp(a). There's no use in talking about Lp(a) as long as Horizon is not reported out. No small particles, I'll stop shortly at that. But the 100% increase in HDL, what is the consequence of such elevated HDL levels? Now first of all, this is part of another presentation that I'll be holding at the U.K. -- at the ESC about the U.K. Biobank. There's a lot of epidemiology out there that tries to kind of make very high HDL look bad. I can tell you with great certainty that that's all BS. It is total -- it is science that is so flawed and so biased.

In fact, all high HDL in humans is caused by alcohol. And so first of all, it's very rare. Only 0.5% of men had it and about 2% of women had it. And so this analysis not published yet to be presented at the ESC shows you actually in orange is alcohol amount consumed per day. And then you see above that HDL. So HDL from 90 to 100 from 100 to 110 from 110 to 140 above 140. These are people not on a drug.

These are people in the general population with HDLs above -- and you can see in dark blue that this is all explained by alcohol. So if you read another aicopal warning on that high HDL is not good for you, remember my lecture and ask him whether this was adequately controlled for alcohol use because it never is. It actually never, ever is.

So the mortality associated with high HDL by observational studies is explained by alcohol-induced multisystem disease. Not only that, the reverse is actually true. So this is -- if you look at the Alenneideran population on high HDL and FpoB, you almost see the same graph because we use the same database -- he went to the 0.5 million people in the U.K. biobank. We went there, and this is the relation between MACE and HDL. You can see that it starts at 30 to 35. That is -- that's not good. It's the first.

But then if you go down, you can see there is no flattening of the curve at all. In fact, the higher you are with HDL, in fact, the better it is. So HDL levels are associated with less risk for MACE and less risk for all-cause mortality. And that is very hopeful for our drug because if it's true in epidemiology, I know you have to prove it with trials, but it becomes a very attractive hypothesis that if your HDL goes up, that the relation between FOB and MACE changes and actually shrinks. And that would, of course, have consequences for the hazard ratio.

Last thing, people saying, I mean, there are all these gold and old that say, yes, but CTP inhibition, high HDL, it's not safe, it's not safe. Well, I don't know how much more evidence you need.

This is REVEAL, 30,000 patients followed up for 4 years, 7.5 years and now 10 years. This is the line of unity in the middle. This is every imaginable side effect that you can come up with, and there's nothing that is either on the up or on the down. So HDL was increased by 100%, and there is no single fatal or nonfatal event that actually was increased in these patients, 30,000 patients. So I think the debate on whether high HDL, when you increase it to a high level is safe is with these data as far as I'm concerned, totally over.

So when we take all that biology, Michael and I and the team decided to, yes, go with the evidence. Our trial program coming next is going with all of that evidence. And these are the names. And I have to say that they're all Dutch, but I didn't invent any of them. So I actually didn't come up with these names at all. Michael came up with Spinoza, and I think RUBENS and REMBRANT came from other people in the team, definitely not from me. So these are 2 Dutch painters and a Dutch philosopher, Jewish Dutch philosopher on the end. It's always it tees the Americans a bit. But these are the names. And I'll tell you what this is.

I'll start with REMBRANDT. I think everybody knows REMBRANDT. What we wanted to show because we have an outcome trial for obicetrapib monotherapy, but what did we have in outcomes for the fixed-dose combination? We didn't have anything. So we wanted something, and that is REMBRANT. We wanted to show that the fixed-dose combination also had an outcome. And here, the outcome is plaque. And you know -- I mean, this is booming, booming business, plaque burden, noncalcified plaque burden. So tandem, 50% LDL lowering, just so the fixed-dose combination lowers LDL at least by 50%. So PREVAIL is for the ultimate question about risk and benefit. But for plaques, we didn't have plaques in PREVAIL, so we needed plaques. And for plaques, we did REMBRANDT. So we didn't start right away.

So we first went to a humanized mouse model and actually checked whether our drug in a humanized mouse model lowered LDL and non-HDL and it did. And then we went and looked into plaques. You can all do that in mouse models. But we were only interested in severe plaques, type 4 and type 5 on the bottom. And the data are stunning and they're published. So in fact, the combination of obicetrapib and ezetimibe lowered lesion area around the aortic route by 98%. That's kind of knocking it out of the park. And then on lesion severity in brown is the fixed-dose combination, green is ezetimibe and blue is OB alone.

But look at brown because that's the combo we're using in REMBRANDT, 97% less of the most severe lesion. And this is exactly the lesion you want to fight because the earlier lesions, they don't give events. It's the advanced lesions that give the events. So we had the biology, we had the preclinical work. And so then we decided let's go for a trial in humans. We already know that our fixed-dose combination did great in terms of goal attainment. This is new data.

What do we do if we use the on-treatment analysis, look at less than 55%, 82.6% goal attainment for the fixed-dose combination. That is just as good as better as anything that is currently on the market for LDL lowering. So this is a number that is outstanding. And with that number, we now hope to show in this trial where we randomize 300 patients to the fixed-dose combination or placebo for 18 months and actually in 18 months, which will be, I think, in '27, end of '27, we'll have the data. So why is REMBRANDT so important for us?

Look on the right-hand side of the slide. There is a lot of increased utilization of this methodology, CT-Nngo for the diagnosis of cardiovascular disease. There's a lot of positive traction with this with cardiologists, and we have designed it to demonstrate the clinical benefit of the fixed-dose combination.

And last, important for you guys, this may support labeling as well as promotion. You can see it moving in that direction. And why do I say that? Because the technology just last week got FDA approval. So we are working with this technology and this company, Caristo in REMBRANDT.

And then suddenly, we actually didn't know it. They, the FDA said, this is approved. Your new CCTA imaging technology is approved. So this is the technology we're using in REMBRANDT. And so we are really, really looking forward. If you look at the preclinical data and you look at the LDL data and if you look at the numbers of patients that we get to goal, this is one of our crown jewels, REMBRANDT. And here we are fully enrolled.

Our operational team is the best of the best. They've always delivered trials earlier than promised with more patients than anticipated. So we have 323 patients enrolled in 50 sites across 7 countries and estimate the trial completion is in 2027. So everything going to plan. Then, of course, we need a small discussion. We've discussed now the plaques, the non-lipid plaques, REMBRANDT and everything there. There is still this small LDL particle and diabetes issue. Now we've shown you in the previous publication, and so this is all published, is that if you pull BROADWAY and BROOKLYN that there is a 23% reduction in the new onset of diabetes.

And we are not the only CETP inhibitor. In fact, all CETP inhibitors showed a reduction in type 2 diabetes. And why is that so important? Because you will, in the future, almost always add a CTP inhibitor to a statin. And what do statins do? They increase the risk of diabetes.

And that's why obicetrapib is an ideal companion to a statin because the increased risk of diabetes by the statin is mitigated by the CTP inhibitor, and it's not a little bit because 23% is actually 1 in 4, that is a very, very significant number. And for that, we designed the Rubin trial -- and why did we design the RUBENS trial? Because patients with metabolic syndrome, obesity, type 2 diabetes, insulin resistance, basically all the same syndrome, they have a lot of small particles. They have statins on board. They have elevated LDL and they have diabetes by definition, Otherwise, they couldn't own the trial. All of those components are being addressed by OB. So we call that the sweet spot.

So these patients are truly the sweet spot. They are very often the patients that are not at goal. Their type 2 diabetes is not resolved. It's not solved or addressed adequately by the current drugs. And they have lots of small particles. They get heart attacks much earlier than people with just elevated LDL cholesterol because they have and abnormal LDL, small particles, insulin resistance, toxic, central obesity, et cetera, et cetera, et cetera. So these patients are ideally suited for a trial with our drug. And so that is what we planned.

The question is, how might obicetrapine reduce diabetes risk? Answer is very, very simple through HDL. It's very simple. The higher your HDL the lower your diabetes risk. So if you double HDL cholesterol, and I can go into the biology, but I won't, you can take it from me that if you increase ApoA1 and small HDLs, you actually basically efflux cholesterol out of the pancreas and you make these cells survive longer. So you address that, you improve that.

And then the science behind the small particles, it's also very simple. In diabetes, you have very high CETP. And if you have very high CETP, you have more small particles. In fact, remember those Japanese, they had no CETP and no small particles. So if you knock out CETP, you knock out the possibility to generate small LDL particles. What do statins do? Statins are fantastic drugs, but look at the right-hand bar, minus 57.5. Those are large particles. So highly interesting, statins lower preferentially large particles. They're great LDL-lowering drugs, but all of the cholesterol they get rid of is in large particles.

So what remains in the statin-treated patient are the small particles. So another motivation to use obicetrapib in these diabetic patients, you're not only addressing their diabetes risk, but you're also addressing the small particles. And all of those questions, we would love to answer in Rubin. This is a pooled analysis of the small particles in our Phase III program.

Look at the light blue bar. If you're diabetic, our drugs lower small particles by more than 90%. So an incredibly powerful effect on small -- so the biggest portion of the cholesterol that is lowered by obicetrapib sits in small particles. And so RUBENS is designed to test all of these effects of obicetrapib and the FVC. So here is the design. 100 patients will go into Oi, 100 patients will go into the fixed-dose combination and 100 patients will go into the placebo arm.

So again, concentrate on the right-hand side. We have a large underserved population, type 2 diabetes metabolic syndrome patients. These patients, of course, there's a lot of traction with endocrinology and diabetes in contrast to REMbrA, where there's traction with cardiology. We have RUBENS designed to evaluate changes in LDL, small dense LDL particles, Lp(a). And the last thing, again, not the least important, it may support LDL lowering in a type 2 diabetes syndrome population in the label. So both trials, REMBRANDT and RUBENS are designed with the hope that we can get some of these data in our label in the United States.

Now I will end, and I hope I didn't kind of bore you to death. I'll move now from the heart to the brain. All our focus is on PREVAIL. So don't worry. Don't worry that Michael and I are going like to scientists with a black hat on an attic and we're going in a direction where nobody wants us to go. Everything is on PREVAIL. But I think that a lot of our hearts actually, although it's in the brain, our hearts is actually in this. So what is this link between cholesterol CTP and Alzheimer's disease? There is very, very old data to suggest that if cholesterol in your brain goes up, the chances of Alzheimer's also go up. And this is not when you're 80, this is when you're 40.

So more and more scientists are beginning to understand that when you're an E4 carrier, that something is going wrong in your brain already in your 40s, and it's extremely mild in the beginning, but there is accumulation of cholesterol in certain cell types. And that cholesterol, when it sits there long enough, becomes oxidized like anything in nature, that leads to inflammation and that starts a cascade that ends with Alzheimer's disease. takes 30 years. So that realizes -- and I can tell you one thing, it's easier to intervene when you're 40 than when you're 80 and everything is basically finished up there.

So this is one very important thing. I'm sure you'll see more and more reports where there is cholesterol dysmetabolism in the brain as the ultimate basis for Alzheimer's. The second is that ApoE4, the most important risk factor for Alzheimer's disease, and some of you who cover neurology will undoubtedly know that, is also a risk factor for heart disease. The neurologists don't know this, but E4 is coming out of our field. It was a lipid scientist who discovered E4 a long time ago, and he published a lot about it. It was actually from Los Angeles.

There's a whole institute named after him there. And he understood that E4 is a risk factor. And later on, it became clear that it was also a risk factor for Alzheimer's. So what is the evidence that low CTP and E4 are intermingled in Alzheimer. Well, in fact, there is very good evidence. There's very good evidence that if you have low CTP that your Alzheimer-free survival is better, right-hand panel. And on the right -- and on the left-hand side, other forms of dementia that are also ApoE4 driven are seen in lower frequency when you have lower CTP. So there is very good evidence coming out of genetics and Mandelin randomization data that low CTP protects the brain, especially if you're in E4. So Michael will tell you that it makes a hell of a lot of sense to get these E4 carriers before they have Alzheimer's. and then start these trials.

Now unpublished data, but what biomarkers are best and of course, p-Tau-217. We now have a link between p-Tau 217 and amyloid and tau PET and between amyloid tau PET and cognitive decline. I think the FDA is very close to allowing p-Tau 217 as the biomarker for Alzheimer's disease. I don't know, maybe even next year. But what did we discover in BRAWY, and this is being presented and published pretty soon. In these patients that were all heart attack patients, a lot of them actually had elevated p-Tau. So something that nobody realized was that in our outcome trials, approximately 40% to 50% of people are on their way to neurodegeneration. So there's a lot of hidden Alzheimer in people that are 70 and have had a heart attack. And it's not that strange because a lot of the risk factors are similar, but that it would be so incredibly high, 45.9% with abnormal p-tau levels, that's truly amazing. And we are writing this down, and it's presented.

And I mean, everybody is fascinated and you'll see many cardiological cohorts repeating this analysis that we did for the first time in BROADWAY. And then, of course, in BROADWAY, did we do anything on these ApoE biomarkers? Last slide. In ApoE4 homozygotes on the right-hand side, p-Tau 217 increased over 1 year by 12.67% and decreased by minus 7.8% in the OBE arm. That is a 20% difference, highly statistically significant. So low CTP protect against Alzheimer. In people with heart attacks, p-Tau 217 is very high, abnormally high. If you give OBi, these levels go down. So that shouts or cries for a prospective trial to solidify that and then understand whether it's worth going into the next phase.

And I hope that you leave with that notion that this intriguing drug that started a long time ago as something that raises HDL, in fact, moved back to lowering LDL, ApoB, non-HDL, small particles, oxidized LDL, small dense LDL and then was found out to also increase Apo(A1, ApoE,HDL, lower Lp(a) and the whole works. And this is kind of the last bit of the almost story ferry tale of what started as something very simple, in fact, is something not highly complicated, but I would say highly fascinating.

And with that, I would like to give the floor to Michael, who's going to tell what you really want to know, and that's about PREVAIL, of course, and also about where we are planning to go with Alzheimer and how we kind of handle that. Thank you very much.

Thank you, John, as always, for the great science overview. And I know this is, I'm sure, on all your minds, and of course, it's on our minds about how we can look at PREVAIL as we have our blinded data ongoing, improving our success with this trial.

So I think it's important to take a step back and talk about the history of Amsterdam and how the PREVAIL study was initially designed. So I think all of you who've been following us for all these years know that we started PREVAIL at the same time as BROADWAY and BROOKLYN in Tandem, 3 Phase III trials along with the cardiovascular outcome trial without having enough funding to complete the trials. We had to realize we had to raise money along the way.

So we designed PREVAIL we think an excellent design. It was 10,000 patients. Again, a lot based on the REVEAL upper tertile as John went through with you, understanding the relative risk reduction in that population, looking at the various 4-point MACE endpoints and thinking about the powering of that trial, we felt we were in a good spot to achieve a 20% relative risk reduction, again, knowing the background of REVEAL and our more effective LDL-lowering treatment with obesetrapib. That was -- we thought was a really good design, 10,000 patients.

And we decided instead of having a much larger trial like FOURIER, for example, which was close to 30,000 patients, like 27,000 patients, we would go -- instead of having bigger study, we go longer to achieve a number of events. You can have more patients or go longer to achieve the same number of events. So that was our initial design. The BRODWAY trial comes out and fortunately, confirming our hope for a relative risk reduction. It was 21% relative risk reduction and the 4-point MACE that was the CTTC kind of standard event rate, which we'll talk about in a minute. And then we were able to raise a significant amount of funding.

And with that funding and looking at the BROADWAY data and the event rates that we had predicted, we wanted to move beyond the 20% relative risk reduction and look at a 15% relative risk reduction powering because now we have the resources to do that. And so that was a decision we made. We announced that, I think, last year at this meeting. But the rationale really is the ultimate value for New Amsterdam is based on a successful PREVAIL.

So we wanted to maximize success and further power the trial, which means we need to have more events to do that. And also, as you're aware, we did modify the 4-point MACE to give us more power. I'll go into that in just a few minutes as well. But keep in mind the background about what we've learned about the previous CVOTs. And we know this, of course, we have many trials to look at. And the higher the baseline LDL, the greater the benefit when it comes to absolute and relative risk reduction. In fact, there's a nice paper showing above 100 LDL relative risk reduction is greater than below 100 LDL risk reduction even if you correct for the absolute LDL lowering.

So having above 100 is a nice threshold to achieve a greater likelihood of success. We wanted to, again, go longer. We saw the mistakes that were made with FOURIER, for example, when you looked at the 2.2-year median follow-up, if they just would have gone -- just look at people that had at least 1 year of drug, they would have gone to 20%, if that was the decision that was made. So it didn't take moving out longer to make a big difference on their relative risk reduction.

And the other, of course, point is the potentially enhanced commercial profile versus other lipid drugs. We wanted to -- we believe that at the end of the day, a successful trial is the most important thing. 15% or 20%. But of course, 20% is better from a commercial perspective. We can utilize that. So we wanted to again enhance that ability to get to the greater relative risk reduction. And those were all put into the design of the trial upfront with PREVAIL. So here's kind of a figure to explain the changes that we made. So we started off with a MACE score definition that was urgent revasc, cardiovascular death, nonfatal MI and total stroke. It was a standard definition that was used by a lot of trials.

Since then, there's been a movement from urgent REVASC to total REVASC for 2 reasons. One is that care has changed, that there's been really a pushback for patients just basically having no symptoms and getting a stent put in. That has changed dramatically with the ACCURGE and the ischemia trials.

Even in the United States, which had the highest kind of intervention rate, we're seeing much more of a change from elective REVASC to not necessarily urgent, but REVASC is driven by symptoms and new onset of symptoms. And so the definition between urgent and and total have become much less of a distinction. Almost everyone now getting a REVASC has symptoms that are increasing. And therefore, it's very close to the urgent REVASC definition.

But yet, when you look at -- because urgent means within 24 hours, you have to have a symptom and get an event within 24 -- get a procedure within 24 hours. Elective technically means they come in, they have chest pain, they get calf and they get a stent that maybe take 2 or 3 days. So that would count as elective. So the difference really aren't that much anymore clinically. So total REVASC and the urgent REVASC and that's been adopted by FOURIER, by CLEAR Outcomes, by Merus -- all the recent trials have moved to a total REVASC, which happens to be the same definition as the CTTC, the broad collaboration of all the cholesterol lowering trials. So it meets that definition.

Now just as an example, Horizon is using urgent REVASC. So it's not entirely completely total REVASC, but it's moving in that direction. Now for MACE-3, which is still very important. I think this is a question we get quite a bit is why -- it is a secondary -- it's our first secondary endpoint. It's an important endpoint, of course, among the regulators, especially in Europe, they want to see the harder MACE endpoints and even the FDA has made comments about that they want to see the overall benefit across all the 4-point MACE. And if the benefits restricted almost entirely in the REVASC, it's a review issue for them. And so that's not that you don't get approval, but it does increase your risk that you want to make sure that you do achieve MACE-3 benefits as well.

And so that's the secondary endpoint. And then we define this more precisely based on what does LDL lowering achieve with treatment. And we focused instead of cardiovascular death, coronary heart disease death, which is fatal heart attack and sudden death. Heart failure death, which is we know is not affected by LDL lowering is taken out of that definition.

Now stroke goes into the fatal, nonfatal stroke definition. So we don't -- we still capture that in the stroke endpoint. So there's a slight difference between cardiovascular death and coronary death, but the precision about LDL lowering is more linked to coronary heart disease death. So we move to that definition. Again, that's the CTTC MACE-3 and MACE-4 endpoint. The nonfatal MI is universal. That's actually the event that is most affected by LDL lowering.

The most consistent reduction is -- if you see the trials, the nonfatal MI rates are what you see the most likely high relative risk reduction. And then in fatal and nonfatal stroke, I'll get to in a minute, but that's an ischemic stroke that we changed that from total stroke. So we don't have hemorrhagic stroke, which we know is not, again, not affected by LDL lowering. So this is, again, the learnings from these trials the changes that have been made in other trials to focus on the LDL-driven endpoints, and that's how we decided to make that change for PREVAIL. So it does add about 20% more events to move from urgent to total revasS. It does make that difference. And so that added more events into the PREVAIL trial to give us more power to achieve that 15% relative risk reduction.

So here is the PREVAIL initiation. We didn't -- we have not purposely published a design paper yet because we've finally got the amendment through the FDA on these changes just recently. And so this is the initial design was the the 4-point MACE, including urgent revasc and the other less specific 3-point MACE considerations. And so we roughly had 1,000 events as our powering for that 20% risk reduction. Again, we had a minimum follow-up of 2.5 years, which we think is one of the most important attributes of PREVAIL. We had a minimum follow-up of 2.5 years. And a lot of the trial shortfalls have been going too short, especially for the minimum follow-up. As we know that after the first year, you don't achieve the benefit that you achieve in year 2 and 3 and beyond.

So the point we want to make, and I think we made this when we announced the interim analysis is that our interim analysis that we are achieving stopping at the December time frame, and then we're going to take time, of course, to adjudicate these events and analysis and so forth. We'll have the data available in the first quarter of '27 to the DSMB to give us a decision whether we met our stopping rules. But that is actually more events than we would have had originally to stop the trial. That's actually more events. And so we have said this publicly also that with the BROADWAY like effect, we feel encouraged that the study will stop at that point with our thresholds that we have not announced publicly, but we're keeping that private because that is important.

So we have, of course, applied in that stopping rule all the important attributes of what a regulatory approval would be. And the FDA is reviewing this and so forth. So this would obviously mean a p less than 0.01 for the primary endpoint and the secondary endpoint also of 3-point MACE also needs to be statistically significant. So those are the important points about the interim analysis. It is, we believe, and I'll talk about why we feel encouraged by that interim analysis stopping the trial. However, most importantly for us is that we want to make sure that we maximize the chance at the end of the trial as well.

I mean that's where we go about to the end of '27, we will achieve enough power to get to that 15% p-value for the primary endpoint of 4-point MACE. That will be 3.5 years of follow-up, of course, a lot more events. And so that is the key decision we made, even though it would take that extra time, we think it's extremely important to make sure that even if the interim does not stop the trial that we have a positive trial in the end. And that is everything that we've done to maximize success. We're doing that with the PREVAIL trial.

Again, the CTP world, as you know, has been one of not good fortune, and we want to make sure we maximize chance of success with the PREVAIL trial in the end. But we -- again, I want to highlight for you why we are encouraged by the interim analysis being the time point where the trial will be stopped. So the first is the BROADWAY data itself. I mean what was exciting about the BROADWAY data is that in the first year, which again, is more than expected, we saw this 21% relative risk reduction. This is the same endpoint that we have in PREVAIL, the 4-point MACE, again, the CTTC definition. So that was 0.79 hazard ratio. Again, the lines are superimposable at the first 6 months. Then at the second 6 months, we see this hazard ratio of 0.66.

And then if we added our BROADWAY to BROOKLYN pool data, we did get statistical significance in that second 6 months. And we're very excited about that when we see the MACE benefit there happening earlier and a greater than expected for the amount of LDL-C reduction, getting to everything that John talked about with the attributes of obicetrapib. So we asked questions. People have asked us what about the breakdown of the different events. And yes, it was driven a lot by the coronary REVASC and that's what you'd expect in a trial like this. The first thing you see go down is the revascularization rates. That's the most acutely affected thing by LDL lowering.

We know that from other trials. But we also -- we saw a benefit on total mortality in the right direction. The 4 points I talked about, the coronary heart disease death also in the right direction, ischemic MI, of course, that was also in the right direction. The stroke was the one that was really -- not that many strokes, but it was in the wrong direction that affected the overall MACE reduction, but those are small numbers in general. But again, the trend was in the right direction for most of the components of the 4-point MACE, especially for total coronary revascularization. So what about stroke? I know there were people that were pushing us to take stroke out because of this data. And I think with small numbers like that, you don't want to be misled by that.

But we looked at -- again, looked extensively at all the stroke data across all the trials. And what you see consistently is that in the first year, there's really no effect of stroke in these trials. But over time, stroke becomes a contributor to the overall benefit. And for us, we want the stroke benefit in our label. That's how it works. I mean you have to have it in your primary endpoint to get it in your label. And that -- again, if we're talking about a dementia prevention discussion, you talk about LDL lowering for vascular dementia, and we think obvicetrapib for -- hopefully, with our SS bearing out, it will be obvicetrapib for the Alzheimer's-related dementia. And that's what we want to achieve with our continued data from all our trials.

And I can only say that as we track the stroke rates in PREVAIL, I believe we made the right decision. We're seeing low rates of stroke going forward and seeing those decline as much, if not more, than other events that we'll talk about in a minute. So we feel we made a really good decision on the stroke inclusion as one of the endpoints in the 4-point MACE. As the only stroke trial endpoint that's out is the HORIZON trial does not include stroke, which I think is maybe a mistake and maybe why their event rates are lower than expected. Also, they don't have that in their 3-point MACE.

The other point I want to make is that when you look at how does the Phase III lipid trials MACE events correlate with CVOT data in the future. And the concordance is very remarkable that if you saw Phase III base benefit in these trials, then you saw a benefit in the CVOT. So out of 4 out of 4 lipid trials, we saw the same relationship between the MACE reduction in Phase III and the ultimate results in their outcome studies to follow.

So it's another important kind of correlation that we think is worth mentioning. We published this paper recently as well. So now let me talk about BROADWAY and PREVAIL. And again, this is the key reason why we're optimistic or encouraged by the interim. The BROADWAY study was started at the same time as PREVAIL in many of the same sites with the same DSMB, the same -- even more important, the same adjudication committee. So these are all looking at the events in the same way. And as you can see, the risk of these patient populations are very, very similar. BROADWAY was ASCVD. It did have about 10% of patients with filar hypercholesterole without ASCVD, but 90% had ASCVD. PREVAIL is all ASCVD, and it has a little bit higher baseline LDL.

But generally speaking, these are very similar populations. So that means that the event rates in BROADWAY give us a really good signal about what the event rate should be in PREVAIL, especially the placebo event rate of each study and really give us guidance about how our event rates will track over time. And as we shared with you in the past, what we see is, again, encouraging that in the first 6 months, the event rates in PREVAIL track exactly what we saw in BROADWAY. And then as BROADWAY lines diverge, Kaplan-Meier curves diverge, we see the PREVAIL data basically staying in the middle of the 2 lines of event rates. You can see the blinded 1-year event rates are almost identical overall.

And if you look at the components, which we haven't talked about, each of the components are almost identical, CHD death, REVASC, urgent REVASC, you want to use it, stroke, non-fMI, all the events look very similar in PREVAIL first year versus BROADWAY first year, blended event rates between the 2. And then over time, we're seeing these event rates in PREVAIL go down even more, which again is our encouragement about why the interim study will stop the trial with the DSMB review. But not only that, besides BROADWAY, which we think is the best kind of comparator on event rates, again, the HORIZON trial, the OCEANA8 trial, they don't have those comparisons to make. Remember, the baseline LDL Horizon is 60. I think OCENA is probably similar.

I don't know if they've actually disclosed that or not. The 60 LDL versus 100 LDL that we have in PREVAIL has give you a framework of event rates because they don't have stroke in there. We have stroke. Otherwise, the event rates are captured in a similar way. But if you think about a 40-milligram per deciliter difference in LDL, what we don't know -- what Horizon doesn't know is what is the contribution of high Lp(a) in that population. And once you wipe out LDL and you wipe out Lp(a), how much events are being driven without those 2 being present. You have very low LDL, you have very low Lp(a). So that could explain why the event rates are lower than expected.

Again, OCEANA has announced again with the Amgen earnings call that their event rates are lower than they push the study out later. But we feel that Horizon, I know people -- a lot of people ask us about Horizon and what that means for us, and we can talk about more about that in the Q&A session. But we believe, as John has talked about so much, that our drug goes well beyond Lp(a) lowering, which is one of the great benefits of the drug when it comes to cardiovascular risk reduction.

But we believe that HORIZON, whatever it shows is going to be a positive for us because if it shows a trend in the right direction that on treatment would have been better because we know that it's been a challenging study for continued maintenance and so forth for multiple reasons. And if we see a positive benefit of Lp(a) lowering, we -- but it doesn't meet approval or has issues like side effects and so forth, and we become -- we believe the go-to Lpy(ate)lowering drug initially on the market.

So that's something that we're excited about. And we think HorRIZon, no matter what it shows is going to be a very important readout for us. But not entirely, we have our own data at BROADWAY showing 21%, and we see these, again, very encouraging event rates. So that said, I just want to -- not only do we look at BROADWAY, of course, but what we have the advantage of versus other trials is we have a lot of LDL-lowering trials to look at. We also have a lot of other CVOTs that have recently been done that can evaluate event rates.

And FOURIER being kind of the landmark trial that people go to, everyone who designs a trial now looks at FOURIER as the event rates because that was a large trial. It's stable ASCVD, which is which is our population. And you can see the event rates there of roughly 5% and 3%, which is standard what you do for these type of trials.

And then we have SOL, all diabetes, again, higher event rates than SELECT, which was another GLP-1 trial without diabetes. You can see the diabetes makes a big difference in event rates. Now both SOL and SELECT have LDLs around 80 and SELECT has no diabetes, SOL has diabetes. And so you can see the difference in event rates. But SOL becomes -- SELECT becomes for us kind of like the -- we should definitely be higher than SELECT because, again, no diabetes, lower LDL, those are the event rates that we saw for 3- and 4-point MACE. And CLEAR Outcomes is a good -- another good trial to look at the most recent higher LDL in the secondary prevention arm.

But even in the on-treatment arm, when you look at the LDL levels that are more comparable to PREVAIL, we see event rates in PREVAIL ongoing that are much lower than these event rates in the blinded way. So we have a good opportunity to look at across trials. It's always the challenge, but it is a famous joke really is that one a good way to lower your event rate is be a placebo patient in the CVOT.

We take that to heart. We really want to be careful about how we look at the data, but what we're seeing is very encouraging that when we see the lower event rates in all of these trials in a blinded way, we can assume a certain placebo rate from BROADWAY, and that puts us in a set up for success with the interim, but more importantly, at the end of the trial, if we need to go longer to achieve that the powering for completing the trial.

So another question we get is what about GLP-1 dropouts, drop-ins. People are always questioning whether the event rates are coming down because people are starting to use GLP-1s. And I just want to highlight for you why event rates have dropped. It really is because LDL levels have come down quite a bit from the original trials as LDL levels were treated effectively with statins, the newer trials had lower LDL baselines. We're driving LDL levels lower and lower. And so those event rates are primarily -- lower event rates are driven primarily by lower LDL levels in those trials. p

And when you look at across -- if you adjust for that, the event rates have not really dropped at all in the more recent trials. They're pretty much flat. And again, that's the population. This data is really supporting that as well. The levels have stayed stable across the U.S. population and heart disease rates are still as high as they've ever been. So it's not -- it's all an LDL-driven difference between these lower event rates compared to other trials in the past. Again, that's why HORIZON trial is probably lower than expected because that LDL level is so low. Now what would it mean for a drop in the GLP-1 into our trial? First of all, our drop-in rates are low. We're roughly a little bit over 1% per year drop-ins of GLP-1s.

We track that very carefully. Same for PCSK9 is even lower than that. And SGLTs 2 tracking -- again, all these are in single digits, low single digits when it comes to drop-ins to these other therapies that can potentially affect MACE rates. But if you look at the magnitude of the benefit, by the way, we're mostly out of the U.S. In Europe and other countries, GLP-1 access is very limited. So it's not -- it's just a U.S. issue that -- because we're in the U.S., you hear more about the GLP-1 drop-in issue. But if you think about for every patients, 10,000 patients you treat, 100 patients treated, only 1 in 62 benefit from a GLP-1. So for every 100 patients treated, you have a 1% drop-in, 100% 100 patients, you get very few events actually prevented.

We're talking about low number out of 1,000 patients that actually would have a lower event rate due to GLP-1 drop-in. And again, we told you our drop-in rates are very low. So we do not believe this has any impact at all on our overall event rates. The overall event rates are the negligible effect on that event rate going forward. So when we summarize where we believe PREVAIL is going is that we also look very carefully on our drop-in, dropouts of other lipid drugs.

Again, PCSK9 is very low, statin stopping or discontinuing very low. And our off-drug levels are compared to other trials is exceptionally good. So compared to CLEAR Outcomes or FOURIER or now VESALIUS, we looked at all the most recent data. Our clinical ops team is exceptional, and we feel really, really good about the execution of the trial, the quality of our trial and so forth. So we believe that cannot be an explanation for the lower event rates. We're doing everything we can to maximize finding all these event rates.

Now what about the patient population changing? As we said, the LDL lowering across the spectrum, you've heard about other trials. Our LDL is 100. It's one of the highest LDLs of any trial. So that does not explain a lower event rate and in the placebo arm in particular. So we believe this is not an issue about the patient population should be a high risk.

It was designed that way, higher LDLs, high diabetes rates, -- that's what PREVAIL is. And so the GLP-1 drop-in is again, negligible and should have no impact on the overall event rates. And so we have believe, and this is our reason why we're encouraged that it's a treatment effect. And we're seeing a great treatment effect of enbacetrib in line with what we saw in BROADWAY.

I just want to point out that we -- this is our view. Again, we want to make sure at the end of the day, though, we don't jeopardize the overall success of the trial. So we will go to that full powering for that 0.01 at the end, if necessary.

But also, we've been asked about the alpha changes is really not an issue at all. It's not an issue for us. on the statistical alpha spend does not affect our overall success of a P less than 0.01 in any way, shape or form. So I think to summarize all that I hope kind of understand where we were when we started and why we now come to where we are on the PREVAIL powering and design to maximize success. These are obviously difficult trials to do, and we're executing extremely well.

And the most important thing, of course, is overall success. And again, we keep emphasizing that the BROADWAY benefit is what we see in BROADWAY, carry that over to the interim, we'll be in good shape. And again, our predicted placebo rates across multiple trials and of course, BROADWAY give us optimism that, that will be the case.

So with that said, I think we'll open up for questions later from the audience. But I'd like to now just talk about SPINOA for a second because I'm very excited about this, of course. Now John mentioned the name. I'll get to that in a second. But this is a really exciting trial for the ApoE4 patient community. We've been interacting a lot with the APOE4 Alliance, a patient advocacy group.

And Wendy being one of the founders of this group is APOE4 homozygot. Her father has Alzheimer's disease, dementia. And she, of course, is E4 homozygot is very excited to be starting in the SPINOZA trial as soon as it gets enrolled. But this is an example of the unmet medical need here that we really want to emphasize with oetrap.

Now as far as the pipeline is concerned for Alzheimer's drugs, we're unique. as John, we're talking about lipid metabolism in the brain. The brain is totally separate from the periphery when it comes to the blood-brain barrier separating the 2. But the HDL is what crosses the blood-brain barrier. There's no LDL on the brain.

There's only ApoE and HDL. So we're very excited about this modality and obbicetrapib being where it is, we can see that we feel we're in a really good place on the overall landscape of drugs that are being developed for the prevention or treatment of Alzheimer's disease. Now prevention is what we're focusing on. And what's exciting about the field right now is about the biomarkers and how we now recognize that 20 years before cognitive decline begins, there's evidence of the biological process already beginning.

We see p-Tau 217 and other biomarkers increasing, and they have very high predictive rates of going on to develop cognitive impairment. Somewhere between -- based on our analysis, we could -- you have a 15% to 25% conversion rate by having certain biomarker evidence of Alzheimer's disease converting from normal cognition to dementia, my cognitive impairment within 5 years. So it's a very viable population to study to prevent cognitive impairment from happening in the first place. And again, ApoE4 being one of the most important genetic factors, that's 25% of the population. So this is, we believe, a very key differentiator for obvicetrapib.

As John showed you, the p-Tau-217 benefit is quite remarkable, especially the ApoE4 homozygous. This p-Tau-217 data keeps getting better and better. Every week, a new paper comes out, highlighting how exciting this biomarker is for predicting and using it as an endpoint for trials. So we're very excited about where we're going to go with the SPINOZA trial. So SPINOA, where the name came from. So as John said, a famous Jewish Dutch philosopher. I'm Jewish, John is Dutch, so it makes sense that we have a Jewish Dutch philosopher as our -- the name of our trial.

But he was also a revolutionary in his thinking. He believed that religion should be rational. And although he didn't achieve a claim in his lifetime, he is considered one of the most important fathers of the enlightment and how we evolved into thinking about things in a more rational way. And the most famous line about Spinosa, I believe, is when someone asked Einstein, do you believe in God and Einstein, I believe in the God of Spinosa. So I think it's a very appropriate trial that we believe we're going to revolutionize how people think about Alzheimer's and the prevention of that with this study and more to come in the near future about the initiation of this trial.

So that said, I'd like to now bring up BJ Jones, our Chief Commercial Officer, to highlight the exciting times we also have on our upcoming launch of obbicetrapib. Thanks, BJ.

Hello, everyone. Very tough to follow these 2 gentlemen, and it always is. But hopefully, you can see how excited we are as an organization. I am personally in regards to all the tremendous work that's been led by the balance of the rest of the organization, what Michael has led, what John has led, what our clinical operations team has done to get us to this point. And then ultimately, our belief is that we're moving quickly now with a clear regulatory path towards what commercial launch. And so I'm excited to kind of bring you up to speed on the great work that we've -- hopefully, you can hear me now, on the great work that we are actually doing.

So with that, what we'll do is we'll spend some time on U.S. launch preparation primarily. And then I'd also like to just bring you up to speed on the work that we're doing around the European launch, just partnering with Menarini and the support that we're providing to them for what is their imminent launch. And so as it relates to U.S. launch preparations, really, we're focused on what are 3 pillars, and that's preparing the market, preparing the product and preparing the company.

So let's spend a little time on the market and what's happening and how that's evolving, right, in the space. And so Michael mentioned it upfront and just started in the space of CV death is -- continues to grow, right? Even with all the options that are currently in the market. We see that as an epidemic, and we absolutely positively need to do something about it. And we continue to do primary research and we do that with patients. We do that with clinicians as well.

And some of our recent data that's come back, it points to what is, again, what we recognize and know, but this is tremendous unmet need that's out in the marketplace. And this slide specifically speaks to patients and basically how they're reduced or difficult dissatisfied in some sense like with the treatment options that they currently have. And why varied reasons why that type of thing. But basically, 2 out of 3 patients are saying that they are not satisfied with their hypercholesterol treatment. And it really -- the reasons why it kind of fall into 2 general buckets, one of which is perceived or real lack of efficacy.

And the difficulty is patients basically communicate that they're taking their medications, they're still not reaching goal. They have difficulty around that, whether it's just medication or even with the addition of what would be diet and exercise. They're just not achieving goal. And then the other bucket in some sense is safety and tolerability. And generally, again, with use of statins, there's just kind of a consistent communication around how there are issues with muscle and body aches and things of that nature. All those things contribute to what is the dissatisfaction generally. And so what does that mean?

And certainly, our industry recognizes what is this tremendous unmet need. And we see what is kind of just driving innovation. And there are -- as you can see here, there are 7 organizations. I'm not telling you anything you don't know, but 7 different organizations outside of Amsterdam who are focused in this space, specifically around what is LDL-C, and that's PCSK9 activity. And then Lp(a), of course, we have a lot of activity in that space and then combination as well. And what you see outlined below is just kind of a pipeline that shows the momentum. This is all public information, but essentially, it's for those that are currently in market, LI and of course, Merck more recently. But you see where the other organizations are in terms of their relative pipelines and the progress they're making as it relates to their Phase III data and then ultimately, their anticipated approval.

And so the investment in the space by this industry, again, it helps to reinforce what our broad conviction is that there's just this lipid management space is very big and tremendous unmet need and that there's a focus to basically bring what is broader options to the marketplace to address the need for patients. And so how does that translate into general market dynamics? And I continue -- every time I kind of show up with you, I go through this and kind of give you an update on what's happening.

We just continue to see what is this dramatic growth in the market overall. As you can see here on the left-hand side, we see general patient population. And now we've seen that kind of move out of the 70 million into the 84 million or so folks who actually are diagnosed with hyperlipidemia. Unfortunately, over 20 million of those folks actually are not on any whether statin or any LLT. And then over 40 million of those folks, unfortunately, are on a statin, but just are not at goal.

And so what that represents, again, is like 60 million patients out there who actually have a need undertreated or not treated at all. Very robust, good for us in some sense, horrible, frankly, for patients. And so if you look as well at the progression from left to right, we just see the relative growth of the market. And we see consistent growth of the overall market, which represents over 2% growth. And the vast majority of that obviously is driven by statins.

As we move to the right, we see the non-statin market, primarily driven by ezetimibe, but again, at almost 20% growth year-on-year. That's been consistent. And then as we go in to further right, we look at branded, again, now north of 30% on a consistent basis and obviously, primarily driven by success of Repatha. We just saw their recent data that popped out in terms of how they're doing. And we expect, of course, that to grow with the introduction of Merck's oral as well. And so what that leads to then is that tremendous growth in some sense.

And what are some of the catalysts? Well, one of them, and we heard Michael speak about this earlier, it's the recent updates to guidelines. And the interesting thing here, and it's actually a very, very good thing is because those guidelines do advocate for what is more aggressive intervention. And the [indiscernible] data was phenomenal and basically has 2 major things, which is you need to actually start treating earlier and with greater intensity. And so those things will -- we believe will actually impact the market in a significant way. And in some sense, it is represented right in this slide, which on the left-hand side, we look at the number of patients and how the patients grow over time, this represents those patients over the last few years, the addition to the market as a whole.

And on the right-hand side basically suggests that the patients that are currently being treated are actually treated more aggressively over time as well. And that is either like increasing in terms of dosing the statins or and we hope more and more is add-on treatments to actually get patients to where they need to be. So that's essentially kind of what's fueling what is this general growth. And that leads to overall branded growth.

And we go to Repatha just because it's the lead product in the space, but it kind of tells the story. right? And the story is that if you past what's on the left-hand side, we obviously all know the story about how slow Repatha was in terms of kind of getting up that learning curve. But in recent years, we see nothing but accelerated growth in that space, incremental investment and recognizing if they engage appropriately with clinicians and with patients is that they're starting to really penetrate this marketplace.

And they're looking at last year at over $3 billion in terms of revenue. And the class holistically, clearly, will bypass what is $5 billion this year. So I think it just helps us to recognize it's a massive market, but we're barely actually penetrating that space from a branded standpoint. So it's much bigger, much more opportunity we've got to reach patients to actually have an impact. And so let's take a look now at the product.

And again, I go back to the great dialogue that we just had with John sharing the science behind it and what Michael has suggested as well. But that points to, again, what is so unique about OB and OB/Ey. And that is we're grounded in what is a comprehensive program, all the Phase IIs, all the Phase IIIs thus far, right, have been successful. And I want to just reemphasize our confidence in PREVAIL and this, again, it's outcomes-driven clinical program.

As a reminder, we will be the only product that's actually launched in this space that has outcomes available, right, a big differentiator for us. And so we believe that Oi delivers what LDL-only therapies were never designed to offer. And this is what John just walked through in some sense, right? We importantly can address what is the current LLT paradigm. And that is we've got to address LDL-C. That's a priority for clinicians.

We certainly understand that. And with our data, we know with confidence that we can do that with the equivalent efficacy, if you will, to PCSK9s appropriately, we can certainly do that. But we look to change that paradigm going forward. And we'll take care and address water particles, but it's that residual lipid risk that we can uniquely do, right, in the marketplace. And when we can do that, and John also talked obviously about the relative benefit associated with increasing HDL as well, that is a very differentiated approach, right?

And the importance that clinicians actually see in that regard as well, and I'll share some data in that regard in just a moment. But the ultimate question is like where do you all fall in the paradigm? What does this look like? And we believe that it will be absolutely can redefine what is this post-statin therapy for those 60 million or so patients that are actually out there not at goal. And we start, of course, at the very top of the funnel with 84 million folks and then they're with statin therapy, there's 63 million, not enough, but 63 million of those folks are actually on statins. Unfortunately, the majority of them are just not achieving goal. And that leaves us north of 40 million who are on -- again, on medication, but actually not achieving goal. And then we add the incremental 20 million or so who are actually not on anything. Right, which gets us to that 60 million or so.

But that's where we come in is that we want to encourage, right, statin use and get everybody as possible on a statin. But we're the next step. And that's an all in one step. We've got to address like what is the initial objective, which is to reduce LDL-C reduction. We can certainly do that. We just walked through that data, approximately 50% reduction or so, but it's the broader lipid impact it's to differentiate. And that's exciting for clinicians as we start to educate and communicate what is this broader benefit. It's safe and well tolerated, as we know, and it's oral once a day, simple dosing.

So that is, again, what is the kind of this differentiated benefit in the marketplace. We know it will have a big impact. And then going back to that primary research. And we talked about patients earlier. Now on the other side of that, we talk about HCPs. What's their perception? And generally, we ask them, how likely are you to prescribe OV and OB/Easy looking at our TPP versus that, which is in the base in the marketplace. And as you can see, 2 out of 3 HCPs are in the top 3 box, which basically do say they have a high propensity to actually prescribe in that space. And I think it's important to recognize the reasons why, which are kind of communicated through the quotes. But one is on what is not just efficacy, but broad efficacy and the perception of none of them can do what this medication can do, which is target ApoB, non-HDL and Lp(a), which has diluted us in all this time. specifically communication from cardiologists, but that's something that all clinicians actually see relative value in. And then a PCP around safety and tolerability.

Now we have something that is even more effective at getting you to goal with minimal side effects and it's safe to take with your current medications. And then lastly, of course, convenience and it's kind of this holistic approach. I would just say it's a novel product, once-daily oral, easy to use. It targets those harder to fix types of cholesterol, Lp(a), ApoB and boost HCL, which leads to better CV outcomes. Again, lots of feedback. We certainly have many, many more quotes, but it kind of anchors, right, in these 3 different areas. But that shows the relative benefit and the receptivity we expect, frankly, in the market when we join. And so at this point, I'd like to kind of shift a little bit to what's the work that we're doing behind the scenes to help us as an organization kind of evolve from what has been purely development to what is pre-commercial and ultimately will be a commercial organization.

And I have to say this is my favorite slide in the entire deck, and I'm going to take a little -- a moment to kind of introduce this team of mine, which I could not be more proud of. And this is the team that, frankly, can and will get it done. And I believe in the statement upfront is this launch success requires a great asset. We certainly have a great asset. We spent 2-plus hours talking about the great asset. But talent is what really makes it work. And one of the things that one of you said earlier is about, are you going to be able to execute,

[indiscernible]. And I said, absolutely, we're going to be able to execute. And it's because of this tremendous team. So I'd like to take a moment to actually introduce you to my leadership team, this launch team, some of whom are actually in the room as we speak and you'll have a chance to spend some time with them. We'll start with Steve Albers, fantastic human being, better human being than actually you an expert in the space. But Steve joined us at the very beginning of the year. He joined us from Novo in which he spent almost 2 decades there, kind of going up that leadership team, but was most recently responsible for the entire portfolio at Novo, pricing, access as well as public affairs and kind of handles that for us now and found this to be that attractive to actually come and join new Amsterdam Pharma. Fantastic job that he's doing with us already, and it clearly will position us well with that set of constituents.

Next up is Mike Astwick, who couldn't join us today. He's actually over in the U.K., but he is responsible, so essentially ex U.S. And so we partner together on how can we maximize the opportunity in the rest of the world and actually get OBOB/EZ into the hands of patients who need it more broadly. Mike and I actually worked together at AZ a few years ago or so, tremendous broad commercial background. Most recently, he was actually on the Board of Verona Pharmaceuticals. So again, has very explicit experience around how do you do launches right? right, and turn out for what was a fantastic option for them. Next up is Chris DeLuzio.

And Chris and I literally have -- I won't age myself, but we have been together for over 2 decades at different organizations. And what I can say is you will not find a better leader in our industry. And he will actually lead the sales organization as well as our enterprise operations organization. And most recently, we shared success at Biohaven. So he's going to bring that expertise here to bring his network and ability to recruit true talent, right, to Amsterdam Pharma. And next up is Selina Fischer, the newest addition to my team. Serena is sitting in the back and very excited to actually have her here with us, and she's Head of Global Marketing.

And Selina and I have spent time -- we worked together back at Takeda, brilliant mind. We'll make sure that from a brand strategy standpoint, like global brand strategy standpoint, we're on point. And that's the work that she's currently doing even the few months that she's been here. So you get a chance to meet Serena. Next up is Deb Horner. Deb is here as well. And Deb and I have spent time together over many years in many different organizations, but most recently at Biohaven. And what Deb is responsible for is operational or launch excellence, if you will. And she drives what is here and her team drive to PMO. And so she will make sure that not just the commercial team, but the enterprise, the whole organization is lined up and ready for what will be an impending launch. And so it's well on our way of kind of making sure that we build the capabilities necessary to do that and do it effectively.

Andy Sheh, who is the Head of Med Affairs, actually preceded me here at in Amsterdam, but actually has over a 2-decade relationship with Michael. Brilliant mine has helped us build essentially what is this medical affairs capability, has hired and built a tremendous team. One of those individuals, Nancy Orte, is sitting in the back there, who is responsible for medical strategy and kind of our evidence generation, all that activity. And I'll show you some of the great work that Nancy and her team have done in just a moment. And last but not least, Sanjay Keshia, couldn't make it today, but he's actually here, the Head of Insights and Analytics. And so he and his team are responsible for all the great work that we've done on primary research. But importantly as well, it's the analytics piece.

And so building the capability of how do we track and basically get feedback so we can optimize launch along the way. And what Sanjay and his team have also been able to do is work very closely with Menarini to help them upgrade their capabilities in that space, so they can look for an optimal launch as well. So let me spend a few moments on activity that's happening today in market, and that's where our medical affairs education, and we're investing appropriately in that space. It's all around developing what is OB scientific platform and the consistency around that platform, how do we communicate and educate in an effective way and how do we engage with KOLs and the broader clinical community and also continue to build value evidence. And we certainly do that primarily in these 4 areas, which is publications, value evidence itself, field medical and congresses.

And I'll just spend a moment in each of those areas. So on the publication side, and again, I just have to continue to point back to Nancy, who is responsible for building what is this tremendous capability. We are data rich as an organization with Michael and John at the head of it. But what do you do with that data? -- and you build it into what are very compelling papers, right, and publications, and we have over 26 peer-reviewed publications. You see where Brooklyn, Broadway, Tandem have landed in some of the best journals, right, in the industry. And you see basically the overall readership of this. So again, we're represented extremely well kind of in the marketplace. We'll continue to do that, and we're very excited anticipating what are the data associated with PREVAIL in the very near term.

On the value evidence side, it's very important for us to generate health economic data and information. We certainly do that on a consistent basis with our Phase III data. We've built a value dossier or we're building do we continue to iterate around that with the new data and real-world evidence is extremely important. We make sure that we communicate that in all the right platforms. And that's great work that's currently ongoing.

On the field medical side, we don't have many folks out there, but they are doing lines work. And deployed MSL team, we've gone out and gotten the best and brightest who have extensive experience kind of in the marketplace overall. And they target KOLs specifically in institutions, broad scientific leaders. We go directly to payers as well and engage them effectively, and we've done that over time. And at congresses, we're well represented as well. So we're making sure as well as we have a big footprint and our shadow basically is much larger than what is new Amsterdam team.

And then lastly, from a Congress President standpoint, we are really making sure we're where we have to be for all the appropriate congresses, both here in the U.S. as well as over in Europe. As you can see, the major conferences. And then what's really impressive, and hopefully, you agree is that when you look on the right-hand side, the relative number of presentations that have been communicated and built in that capability, again, like this is the outcome in 24, 17 presentations, last year, 40 presentations in this year alone, 39, and we're halfway through the year. So we continue to build again, and have a very large footprint in the community.

So with that, the next thing is branded launch, right? And that's what we're working on feverishly. -- underneath the water, right, just to make sure that we're prepared as an organization. We are very customer-centric. We're going to make sure that we're focused on bringing what is this transformational product to market, as we've talked about. It's tremendous responsibility for us to do that, and we're prepared to do that. And we need to make sure we do it with a seamless experience for all the stakeholders aligned here.

Now I'm not going to go into a lot of detail at this particular juncture as it relates to how we do that. But what I can say with confidence is that we're looking to embed innovation throughout. We know that we can do things in a very effective manner, but do it efficiently. And so there will be efficient spend of resources, and we believe we can do more with less as well in regards to headcount. So we'll get all that done. We know we're in a very big marketplace. We know we'll be battling competing with what are big players, but we feel very confident we can do that and do that effectively in this -- and as a reminder, the market is so big. It's not we win, they lose type of scenario. It is very big, certainly big enough for several winners in this space.

And ultimately, that's a winning solution for clinicians as well as patients. So let me spend just a moment on the European launch update. As we all know, we got positive CHMP opinion just recently, great news and a fantastic milestone, as Michael said upfront, first time for this MOA, right, to get approval by a government body. We're extremely ecstatic about that. If we take a look at some of the similar data, it's very interesting to see that in the EU, the market is actually large but growing even more rapidly than what's happened in the U.S.

And unfortunately, it's because like patients are just not being treated to the degree that they need to. And so you can see the overall market growing at plus 7%, non-statins at 25% and brands at 50% or so, right? And we expect that to continue to grow. And we want to be right in the middle and in the thick of that with OB and OB/Ey. In a similar way, we see kind of early demand for OB reflected in primary research as well in the EU, specifically in the EU5. And these data essentially are a response to your likelihood for prescribing OB and OB/Ey within the first 6 months. It looks very similar to the type of data that we have in the U.S. as well.

So very receptive audience, and we look forward to seeing that play out in the near term. As we look at EU regulatory and launch time line, of course, we talked about the recent opinion, anticipated EMA approval. would come in early Q4 and then anticipated launch in both U.K. and Germany by Menarini at the end of the year, late in Q4. And so I do want to mention very quickly is that Menarini, we absolutely believe we're well positioned to launch Oi. And it's driven by what is this kind of historical CV heritage that they have, leading share of voice and significant local presence. And Menarini, again, has a very broad portfolio and specifically within CV. So they have established relationships, and there's a lot of trust with the call points in that space.

But importantly, as you can see here, and this represents the EU 5, but whether it be general practitioners, cars and internist, like they have extreme leading share of voice in that space. And so they will be where the patients are. And that's a key to success in that -- so we look forward in terms of that partnership, and we're working very closely to make sure that they're fully prepared for what will be launched later in the year. So as I close on this point before I hand it back to Michael, I just want to reinforce the fact that look, if approved, OB-OBZ can and we believe will redefine the post-statin treatment by getting patients first to LDL-C goal, which is the primary, we know that, but we can do that consistently with the competitors out there while also mitigating what is this residual risk.

The significant unmet need we have talked about, very large market, still growing, about $60 million in the addressable market for Oi as we defined, potentially the first LOT to launch. We know we have 3 very successful Phase III studies, but the first to launch with outcomes data in hand. can't express how important that is for us. From a differentiation standpoint, very powerful efficacy, as we've talked about with that differentiation on Lp(a) particles and the rate of new onset diabetes.

All of that within what is a simple oral once-day low-dose solution that's reported to have safety tolerability profile comparable to placebo, right? And the medical affairs team, again, is not just capabilities, but we're actually in market today like with success in kind of spreading what is education to the broader audience. And again, as I mentioned to you, the best team in the business and anxious for you all to get to meet them in the near term.

So with that, Michael, I'd like to hand it back to you.

Okay. Thank you all again for coming. I think we're going to wrap up here and open up for Q&A. So it's important that I think we're setting out here all our multiple readouts coming up, and I want to highlight those for you, the milestones and catalysts that we're going to have over the next few months or years. But I'll start off with this. We're data-driven.

We want to make sure that PREVAIL is successful. As BJ has highlighted and John has talked about, we have a very differentiated drug from any other LDL therapy. The unmet need is big and getting bigger based on the new guidelines. And I hope you got a flavor for what we're recruiting here in New Amsterdam under the leadership of not just the commercial team, which you'll see is exceptional, but across the company, we're building out a very accomplished industry executives. The KOLs are really rallying behind us and very excited about the new therapy. And we also, of course, have the balance sheet to get us through a commercial launch.

So here's our readout kind of milestones over the next 12 to 18 months. Rubens will be this year. It's all fully nearing completion. We'll look to lock the database, and we'll have data at the very end of this year. PREVAIL, we talked about the CVOT. The interim analysis timing-wise is -- we believe will hit the numbers by the end of the year and then the readout in the first quarter of next year on the interim analysis. REMBRANDT, again, a very exciting study looking at plaque, noncalcified plaque as an endpoint, which is again becoming more and more established in the cardiology community. That will read out sometime in '27 and starting SPINOZA. We believe SPOZAH going to go quickly. I mean the feedback we're getting from the patient community is overwhelming. Patients with E4 are knocking on our doors all the time to be in part of that trial.

And then that we believe will be an important kind of part of our whole launch differentiation as well, having that benefit that we've already established with the BRADWAY data. Then, of course, the tailwinds that's been talked about so much this morning, the guideline changes, getting LDL goals now established, Lp(a). HORIZON is important, and we're going to have Lp(a) lowering benefits in our label in Europe as well as HDL, phenomenal HDL data. So this is a -- these are key differentiators of obbesetrapib, getting momentum as a target.

We're all waiting for HORIZON. We see that as -- I think people are waiting for that and affecting our -- but people are looking at us until that data comes out a little bit waiting for that data as a clearing event for us. But like we said before, it's -- we think it's a winner no matter what happens with with HORIZON, get it out of the way and other trials to follow because this study itself may not be the best study to evaluate Olabel.

We believe there will be a benefit there that will support LP lowering, but we believe will also be one of the primary drugs to go to when our drug is available in the market. And we also have just seen this tremendous growth in the market overall that's going to allow us to be very effectively launch the drug. So with that said, I just want to again thank everyone for coming. It's always great. This is, like I said, one of our favorite days to get out there and talk to you, our investor community, our stakeholders. And we love to get your questions and answers, hopefully, good answers for what you're going to try to say in your reports and so forth.

But thank you again for coming. And now we're going to have it right now the Q&A or take a break or ahead and have John and Ian and BJ come up. We're happy to take your questions.

Tyler Van Buren, TD Cowen. Thank you so much for the interesting presentation. A couple for you. What can you say about the decline in event rates that you're seeing in year 2 of PREVAIL on a blinded basis, of course, relative to what is historically observed with CVOT outcomes trials? It would be great to hear you elaborate on that and what gives you confidence?

And then the second question is, can you help us better understand the powering of PREVAIL at the time of the interim analysis? Do you have to report a MACE benefit similar to what was BROWAY in order to hit both MA and MACE at the interim? Or is there a cushion on the lower side in case it ends up being closer to PCSK9 at 15%, at least from a MACE 4 perspective?

Right. Thanks, Tyler. I think I'll let John elaborate, too. But the -- what I tried to portray is that obviously, we're blinded and these are blended event rates. So the first year looks very similar to BROADWAY. And so -- and that's -- again, BROADWAY was designed to derisk PREVAIL. Also one point I wanted to make is that we have -- people have followed us since then, a lot of -- but we were the first to really put all the ASCV patients into one large trial just for this very reason, just to maximize the events in one single trial. We also needed it for the regulatory approval in Europe. They wanted to see MACE rates that did not show harm.

So like the diabetes regulatory process. And we achieved that, of course, now with the CHMP recommendation. But when you have -- no one's ever had the the benefit of having a trial that was done that has basically the same population as your outcome study starting at the same time in the same sites with the same DSMB, the same adjudicate. We never had that before. So if anything gives you a guidance on placebo event rates, it's BROADWAY. And so what we are trying to say is that if we impute a BROADWAY placebo rate into the blinded PREVAIL data, we look really good. We look really good. We won't tell you what the numbers are, but we are seeing BROADWAY relative risk reductions with that imputed placebo rate for both 3-point and 4-point MACE. And so that's how we look at it.

The question about the powering, again, we're not giving away exactly the numbers, but -- we do have some wiggle room. We don't have to be 20%. I mean we could be lower than that. So that's the -- we're not going to give you the exact range, but we don't have to be 20% to achieve the statistical significance for both the 4-point MACE and the 3-point MACE, the way we have it set up. And again, I think we just want to just keep emphasizing that it's really a free look for us.

Again, the look is the same time we would have stopped the trial anyway. We did this to ourselves. We wanted to maximize chance of success. So we could have stopped the trial as planned right now at the interim. But we felt that it was more important at the end of the day that we completely take all the risks as we possibly can off the study to make sure we have a final result that's positive. And that brings us even a lot more power at the end for closer to what you see with the the PCSK9 15% relative risk reduction.

Again, if you look at all the trials, Repatha 15%; and FOURIER, 19%; and [ FRSalIus, ] CLEAR Outcomes, 13%. ezetimibe, 9%. So we want to make sure that at the very least, we have to be powering for 15%. I mean, so that -- we just can't call the trial, we hit something that's 15% and it's not stically significant, that would be, I think, a major mistake. And so it's an extra -- potentially a little bit longer, you're close to a year, but that risk, we think, is -- that delay is well worth it. But with that said, though, we -- like I said, we can't be more clear that we are seeing these event rates that are low for both 3 and 4. Just to keep that in mind, both 3 and 4 that we see these lower event rates that if you impute a placebo rate from BROADWAY, we are in a good place for the interim to hit both the 3- and the 4-point stopping goals. Does that get -- that help you? Okay. right.

This whole discussion is muddied by the fact that Novartis, of course, and some KOLs say, yes, all these event rates are the king in all these trials. What they forget to mention is that if you control for LDL, event rates are not the king at all. And so therefore, the choice for a 60-milligram baseline LDL in Horizon was a wrong choice. They're never going to say that about their own trial. And second, it might be that if you really knock down LDL, that the impact of Lp(a) might be a little less. They're not going to say that either because they're losing the market right there and then. And so the discussion is muddied by that a bit. And then people say, well, all trials, events are going down, so PREVAIL will be automatically part of that. And scientifically, that's real hwwash. It's simply not true.

Event rates have been extremely stable if you control for baseline LDL in these -- by far, the best determinant of event rates in your trial is your baseline LDL. And I don't understand how you can -- after having witnessed REVEAL, REVEAL was a failure, the one I showed because baseline LDL was 60. If baseline LDL would have been 90, they would have a 26% reduction of that CTP inhibitor. And so what's happening now with Horizon, they designed a trial where the baseline LDL is 60. We have a proper for that in Dutch, but I want to here.

Thank you for always an excellent presentation of science commercial outlook and really connecting the dots and learning a lot. Three really simple questions for you. One is, what is the probability that the interim concludes -- and you don't need to go until year-end next year in your view based on the analysis that you have done. Question 2 is, why not do the interim and just keep going until end of next year and report out you have more events occurring, greater probability probably to see a greater separation. And then the third one is, Ian, how do you envision the disclosure going to look like at the time of the interim? What can you tell us at that time point?

We're not going to answer any of those.

All right. Next question.

From Michael.

The question, why not just do the study at the end? It's a good question. I think the -- and we debated this, of course, a lot. And then the interim, though, was 2 reasons. One is the data that we're seeing. We're seeing the blinded data, and we're getting very encouraged, okay? So that helps make that decision on the interim.

Secondly, is BJ tapping on my shoulder saying that you wait another year, you got Merck and Trenchmore AstraZeneca launching, your commercial success is going to be more difficult. more challenging. And so that also has to go into our decision-making. But more -- it was mostly about the actual events that we're seeing. That was the main reason for the. We didn't even think about interim until we start seeing the events going down so significantly. And so that to us was the key reason. We -- I think the most important thing. And then again, of course, the alpha penalty, if you want to call it, is actually nothing for us. I just want to keep making that point.

The actual study 0.01 is not impacted at all by the alpha that we have to take for the interim. So there's no penalty at all for the interim analysis for the study. So I want to make that point. Credit, you can bring that up as well. And so that's the other thing we're going to bring out. But I think it is about -- we do have an extra roughly a year to launch is -- has an impact with the competitive landscape out there that we have to also consider.

And I guess from a finance standpoint, as Michael said, when the trial started, the company had a very different financial picture to where we are today. So we have the ability to invest a year and if we need to, just further preparing for a launch. So it's just -- it's having all those pieces in place. And from a disclosure standpoint, once we're notified by the DSMB of their decision, we'll share that with you. Separate from that will be the actual number in terms of the MACE benefit. But again, we'll be as transparent as we have in the past. That's a policy that we're not going to change.

Steve with Cantor. Just a follow up on the blinded event analysis. When you project the placebo arm that you were talking about doing from BRODWAY and maybe from the precedent studies, do you assume that itself slows down in year 2 and year 3? And to what extent? And maybe talk about like what is informing how you model that?

Yes. There is like the K you apply to the placebo arm also, and there's different ways of looking at placebo decay, but we have accounted for that in our analysis, yes. And you have an average. In some studies, the K is -- the 3-point MACE decay is a lot less than 4. And so we study this very extensively A lot of AI is terrific. We have a lot of data that we could analyze for decay rates of placebo arms. And so each study is different a little bit, but we even take more extreme examples, we feel we're still good on the blinded event rates.

So we've been extremely conservative in actually building worst-case scenarios. And even in those kind of simulations, we still feel very good.

Okay. And maybe this is for BJ or anyone who wants to answer, but curious if you have any updated insight on pricing decision for Menarini or just maybe framing expectations of how this would be priced in Europe and trying to calibrate us for what should be modeling here?

Yes. If you don't mind, I'd actually like to maybe introduce Steve and let the kind of respond to this, but don't get your hopes up because we're not going to share...

I want a way to meet you all. I guess the parent...

We're not going to answer any of those questions.

It is really too early to speculate or put anything out there about where we see Menarini's pricing. I would just say coming back to the commercial presentation of Vijay, like when you think about the size and scale of this market, the opportunity to reach millions and millions of patients with a differentiated asset, that's what we're really super excited about. So without saying anything more, I'll leave it at that.

From RBC Capital Markets. I just want to make sure BJ does get some airtime here. So I guess maybe a 2-part question for you. I guess the team is obviously really excited about the OBS-C combination, but in the survey you showed, it didn't look like physicians had a higher intent to prescribe. In fact, it just incrementally lower. So I guess how do you square that? And then the second thing I wanted to touch on was Merck's label. They got a label that had no AE table, an implied CVOT benefit. I guess how do you think that informs how you're expecting your label look and ultimately how you maybe detail again Merck?

Sure. And sorry, if you don't mind, I'm actually going to pass that baton over to Selina to give her a little airtime on this. But specifically around question number one. Question number two, I think I was probably -- maybe to Michael.

The label.

The relative impact on the label.

Yes, the label was -- Merck had a really good label. That's great to see. I think it's good because that will also carry over to us. I mean they are -- that's one of the points we want to make is the labeling is getting more -- payers are using labels for restricting access and that label, I think, for Merck is a terrific label. The give them a lot of credit for the label that they got.

And I think that, obviously, we hear what Amgen is going to do. They're going to hammer their outcome data. They're going to hammer the dosing regimen and the food effect and all that kind of stuff. And so it will be between Amgen and Merck, oral versus injectable and all the issues that go with that. We believe a very fundamentally different value proposition for obicetrapib.

Again, we tried to show the on-treatment analysis today to highlight for you that our FDC with ezetimibe, we're in that 60% range also. I mean we're in the same LDL lowering range with our FDC. So we have a much easier to use, well tolerated. So we've heard -- I've heard this feedback from a lot of folks that Oi is a kind of a good utility field, but not as good in LDL or not as good as Lp(a) lowering as Lp(a) lowering drugs will be.

And I take that, that's potentially a little bit true. But on the other hand, what I would say is that what Oi provides is -- if look at the patient journey experience, again, I speak from my own experience, when you prevent diabetes, when you lower Lp(a) without the injection, but in that range where Lpy()lowering therapies are not going to be available or not approved, and you potentially prevent Alzheimer's disease, that becomes a drug that instead of I have to take this drug, they want to take this drug.

I can say that for sure that this is a drug that people are going to want to take as opposed to have to take because the doctor takes them take it. That -- those are the differentiations that no one else has. And so again, I think it's going to be a great differentiator. And again, Merck is going to help grow the market.

We're going to learn a lot from the Merck launch that's going to help us a lot when we launch our drug. And so I'm looking forward to how that drug does. You'll be using it a lot in my lipid clinic as well, I'm sure. So I don't know, Serena, I didn't want to take away your thoughts Yes, I don't know if I can add anything.

It's wonderful, Michael. Thank you for the commercial mindset in addition to your clinician perspective. So the data that VJ showed, we actually have a number of different cuts looking relatively similar in terms of their interest in using either the monotherapy or the FCC. In fact, from our early demand studies actually show that -- we do believe that the FCC will primarily be used on physicians. This is -- you get that innovation in OB as a first-in-class new mechanism of action potentially that we'll see there.

But then we've got the opportunity to add an FCC with an already trusted well-known tolerable option for individuals. So this is that synergy that we start to see where other lipid-lowering therapies just weren't designed to do that. So we think that, that makes a very safe, effective, tolerable option that clinicians are going to be very comfortable with. So hopefully, that helps to address that question on.

Maybe I'll start with a question for P.J. then.

We know where the oral PCSK9s are priced and you know where the injectables are priced. When Oi launches, you'll have your outcomes data. Does that give you more wiggle room on the pricing compared to the oral PCSK9?

I would say the following, and please correct me if you on this one to jump in. But we have to see, obviously, what happens with Prevail for sure. Is there opportunity for there to be some premium in that regard based upon the outcome? Sure, right? But I can say with confidence is that Merck and we're still watching what happens here, but they came 50%-ish, right, or 40% like reduction in terms of WACC, right, compared to injectables.

But we're watching very closely in regards to rebate structure, right? Again, we don't think that they're doing anything to undercut the value in the market holistically. And so we don't see that as a negative at all for us. But Ian, anything else you want to add?

The only other thing I would add is just focus on the size of the market. I think as I hear your questions, it's really looking at the model and what kind of drives value. The biggest source of value is the sort of the unlimited number of patients that are out there and the opportunity for all of us as well as other companies that are in the space to be quite successful. And it's a point that you've heard from several of us today, this is not unprecedented. We've seen this in this market before.

The opportunity in light of the labeling changes that Leo just asked about, this is something that's been going on for 2 years now. We first saw the FDA expand label to include patients with really anyone with elevated LDLs, no longer restricting it to secondary prevention. We also saw expansion of sort of MACE indication.

So I think it's an alignment of all the factors that we could possibly have to support a launch is successful for all parties. And that's what gives us really ultimately confidence in being successful commercially. So one of you wrote to me, BJ has probably one of the easiest jobs ever commercial launch for selling a drug, but we know that's true. you'll do better question.

And just one more then for Michael and John. Given what we know from the Horizon baseline and the difference in MACE on the endpoints, what does it mean for your interim if Horizon reads out with a 12% risk reduction or fails?

The CEO said that 13% to 15%, he would consider a win. So why did you choose 12 I think that a signal that for Novartis would be a disappointment in terms of its effect size would for us always be a win. So we just want to see the principal horizon for us, of course, I mean, for patients and for everyone will be fantastic if it would be 21 or 19 or 20, then all -- I mean, all hands down. But if it would be 14 or 15 and just not meet statistical significance or not enough so that there's a lot of discussion at the FDA and at the CHMP, it will be still good because everybody would expect after that, that Amgen would kind of make the final goal.

So that, I think, for us would be very good. I just -- what we need from Horizon is a biological confirmation that lowering Lp(a) makes sense. That's -- it's kind of the bottom what you would want to see. Now it's very different for Novartis and Ionis, of course, but for science and for New Amsterdam, we just want to say that -- see that it makes biological sense.

If I could add, and please correct me, both of you, for PREVAIL to be successful, all we need is to reduce LDL by the magnitude that we've already reported. So the Lp(a) is an incremental contributor.

And we've already shared with you, obviously, the outcomes benefit that we saw in BROADWAY. So the explanations might change. The reason behind the outside benefit from BRAWAY and what we could potentially see in PREVAIL. But I just don't want you to connect those 2 dots, PLO and Horizon represents PREVAIL...

We never took any of that into account when we looked at PREVAIL. We look at PREVAIL, we look at numbers. And the numbers are the numbers. There's no explanation as to why behind those numbers. We did it in BROADWAY because you can't control yourself. You want to do a mediation analysis of results. That's what everybody always does. And there are some hypothesis generating thoughts coming out of it. that include Lp(a) small particles in HDL, which is logical because that's what the drug does biologically.

But if you look at PREVAIL, you don't need that because you just look at numbers. And as Michael was saying, the numbers give great confidence. And then we'll see. But Horizon, in essence, just needs -- for me, just needs a biological kind of confirmation. That's it.

I think we made this point before, but if you look at LDL, non-HDL ApoB, just look at those alone from our BROADWAY data imputed into PREVAIL, the benefit at BROADWAY. We're at 17% to 23% risk reduction. And so that's without any other plus benefits. So that's the if you look at REVEAL, which is John tried to show that 17%, if you adjust for how much more LDL non lowering we have, we're above -- we're in that broaday plus range on risk reduction. So -- and then -- so that -- those are 2 ways of looking at it.

And then the other way, of course, is what we're seeing now live on the event rates and how we can impute a placebo rate into our blinded data and come up with numbers that look promising for stopping at the -- but at the end of the day, we don't count for anything. We take -- to Yas's point, we don't -- why not go all the way -- go to the end, we'll go to the end. I mean, so we can get the relative risk reduction that's a positive trial. I mean that's what it comes down to.

And maybe the one final factor is the operations of the study. And I think we've shared this in the past, we didn't do it today. It's -- our clinical operations team has just done a phenomenal job. So as we track metrics from a standpoint of patients on therapy dropouts, drop-ins and so on, we compare quite favorably. So that's the other sort of unknown or factor that could play a role. And I think our team has done a really good job of managing that.

We're doing way -- I mean, that's an understatement for we're doing way better than any recent other trial.

Very thorough answer. So I'm going to throw in 2 other questions Anna Ruiz from Leerink Partners. So just stepping back, just thinking about all the historical CVOT data that you've leveraged so far, I was curious if you have any updated thoughts on some of the recent CVOTs that have missed, including oos. Obviously, different drug, different target, et cetera.

But are there any considerations we should think about framing that against PREVAIL and building your conviction there into the interim? And then second question is just if everything works out, let's say, PREVAIL stops early for good efficacy and you also have positive data in hand with Rubin, how should we think about the implications for OB and the FDC label and how physicians would interpret that?

You do the second. So -- so what is unfortunate at this time is that, of course, if Zeus is negative and there are discussions on the horizon that people think outcome trials are not working. And that's not good for us because we have an outcome trial around the corner. But that's a very muddied discussion. First of all, Zeus simply did not answer the no hypothesis. And I have not seen a single tweet. I don't -- I know it's not called tweets anymore, but I haven't seen a single tweet or heard a single podcast that gave me any reasonable explanation as to why this happened. So basically, no one knows. So it's truly you have a no hypothesis. The trial is completely negative, 0.99 and then everybody is like flavorgasted. I mean, Peter Libby held grand rounds at Harvard Medical School 1 week ago.

And Sanjay Koul wrote me a tweet, he said, that did not mature well because 1 week later, the trial was negative. So I mean, even the brightest minds on inflammation did not see this coming. So we can certainly not see this coming. And -- but it's a separate entity. Horizon, we've already discussed. So I think both Horizon, I mean, definitely Zeus has nothing to do with PREVAIL at all. I mean the null hypothesis for CTP inhibition is already answered by PREVAIL and the genetics and the Mendelian randomization studies and everything else. There are 4 Mendelian randomization studies showing that low CTP leads to less heart attacks.

So we're not worried about PREVAIL being positive. The real issue is how positive, of course. And Horizon, I think we've already discussed. So those are very different things, but sometimes people keep them. And then it becomes, of course, negative for us, which is a bit uncalled for because it has no -- one has nothing to do with another.

I'll add a little bit because obviously, this is very disappointing. But I do think we'll have to wait and see what the data tells us, but it was a pretty sick population. And I think that's one of the key things about all these trials is that you have to treat the population with the modifiable factor that could still make a difference. like I said, if we -- Alzheimer's is another good example. I mean, if we had started using lipid therapy for heart failure reduction, we never would have seen a benefit.

And so that's the point. I mean, you can't go too late. I'll have to wait and see what Zu says. But I have a hunch -- it was a very -- we know it was a sick population, a very high event rate, very high mortality rate. So it just could have been too late for the population to benefit. We will have more with the ARTemIS and Hermes to come -- I think it's -- but it's unfortunate for the field. We'll have to wait and see what is American Heart.

To your other point about the diabetes Rubin study, we're not getting -- we don't -- we're very excited about it because for a couple of reasons. One is that it is a prime differentiating population for OB. If you -- again, talking about my experience in the clinic, patients are definitely afraid of stats causing diabetes. That's a known effect. It's a known effect.

In fact, the paper just recently came out that the risk of diabetes was up 25% when you're in a high-intensity -- so there -- patients come to you, they're using AI just like we are, and they know that statins cause high risk of diabetes. OB has that benefit. Again, it may not be in our label, it prevents diabetes, but the RUBENS study, what it presents is an opportunity to show how well the drug works in the diabetic patient in the label, not just those with heart disease, but those without heart disease. And as you know, that's the VerLesS population benefit is quite dramatic in that population as we believe that's a population to focus on for primary prevention that's very large.

And so we see this as a chance to get into that broader population in our label with the Ruben study. So -- and also it is the good fortune that Oi works better in diabetic patients than does in nondiabetic patients. So we have another chance to get an LDL lowering benefit that's in our label that is higher than what we have already, and that gives us a chance for BJ and his team to promote that. And so those are all, I think, real positives to RUBENS that we'll see relatively soon.

Matt Phipps, William Blair. You outlined the number of events that you expect the primary to be greater than 950 for MACE-4. What should we expect for MACE-3, 60% of that? And with the lower event rates, should we assume there's a greater alpha spend to hit that MA just given the lower event rate to accommodate for that?

And then on the -- thinking about the timing of an NDA filing at this point, is the options really either maybe mid next year with a positive CVOT included or later next year, knowing the review is going to happen during the full primary readout, which would be available during the review?

So Matt, we're not going to give the exact numbers, but we had those greater than signs on purpose, like had 2 greater than signs a before the 950 at the interim, just so you know it's going to be more -- quite a bit more than what we had at the initial study readout for both 3-point and 4-point, obviously.

So -- but we can't give you the exact numbers because people reverse engineer, you get start getting all kinds of questions about -- but we can just tell you what we're telling you that we feel good about what the interim is going to show for both 4-point and 3-point. Again, a BROADWAY benefit for both 3-point, 4-point were safely in the p-values that we need to stop the trial.

So we need it for both 3- and 4-point to be consistent with each other. for that reason. So that's almost always the case, by the way. If anything, 3-point is better than 4 point, at least RSalius it was better 2025 versus '19 or something like that for...

And the spend doesn't...

The office spend is not doesn't bad, doesn't affect us at all actually. It doesn't affect us at all.

Most for the 3-point either.

Yes. Can I take the question on regulatory filing?

No, you're right, right.

I don't want to forget that question. So our plans haven't changed. And this is informed by engaging with payers. What they want to see is outcomes data. They want to know the outcomes data. So the idea of waiting for the outcomes data to file, that's not something that we're considering today. And then related to that is we're obviously engaging with regulatory agencies and specifically the FDA to file the earliest -- at the earliest possible date.

So we don't want to delay the filing as a result, delay the launch. But we're obviously mindful of when the outcomes data will be available as a result in the public domain. So those are the things that are going to inform the overall time lines. It's not a complete answer. I'm sure it's not a very satisfactory answer, but we'll do better.

This is Srikripa from Truist. Thank you so much for the very detailed presentation and John, definitely not boring. So I actually wanted to switch gears a little bit and ask about REMBRANDT. So with enrollment complete right now, just was wondering what do we expect over the next few months? Could we see any interim or blinded data -- how confident are you that the changes that you see in the NCPV will translate into clinical benefit?

What magnitude of benefit would you have to see with the regression to see benefit in CVOT? And I also saw that you're measuring FAI. I was just wondering how you expect that to play out? And if you see benefit in both FAI as well as the plaque regression, what does that say about OB in terms of maybe impact on inflammation?

So I think I have to start a little earlier on the mechanism of OB and ezetimibe. What we saw in the animals first and later in our Phase III program also is that the 2 mechanisms are actually more than additive. So there is a synergy between inhibiting CETP and inhibiting cholesterol absorption in the gut. If you look in the animals, that led to astounding regression of severe plaques and astounding regression in the aortic root surface area.

So what happened in the animals, if you give the animals, which is the best humanized mouse model on the planet, it's the APOE3Liden CTP knock-in mouse that every major company uses that wants to study their anti-lipid drug is that you basically eradicate severe lesions. That goes almost always hand-in-hand with a very severe lowering of the FAI. So those are 2 effects that are not totally separate from one another.

I think that -- and I am not a cardiologist, but I think that in the cardiology community, we are getting pretty close to CCTA being approved by the regulators as an intermediate biomarker that aligns extremely well with outcomes. So of course, this is -- I mean, behind the scenes, there are major institutions in the United States who are working towards that. So I have great hopes that because we are testing not only OB mono, but we're also testing the fixed-dose combination in REMBRANDT.

And we have seen the goal attainment if we do on treatment, and we've seen the LDL lowering and all the other benefits. So -- and then we've -- the preclinical work. So we have great hopes that we'll see very, very large effect sizes in that trial. And 18 months is the right time. I think there are some 12-month studies, but I think 18 months is a better time course. And then we're using the technology that was literally last week approved by the FDA and the company, Caristo, is a company out of Oxford again from a Greek Professor of Cardiology who has developed his whole career based on the FAI. I think it's a bit difficult to discuss this in relation to Zeus because the FAI shows you percoronary inflammation as one of the most important determinants of risk.

And of course, we've just seen that lowering IL-6 actually doesn't do anything. But the -- the FAI predicting risk, I think, is a scientific data that has no questions. So I think what we've done is we have the drug that lowers the parameters that we want to lower to a very large extent, PCSK9-like. We've shown in animals, the most relevant animal model that we eradicate non-lipid plaque and inflammation. Those data are still to be published, by the way.

So we are going to publish that. And so we are now using the most validated technology in the patient population. And I can say one thing is that baseline plaque in those 323 patients is more than enough to show a difference between placebo and intervention patients. So actually, it's my favorite trial right now.

Other than PREVAIL.

Of course, PREVAIL.

Yes. I want to emphasize one point that John said, we do know the plaque levels are high. That was a difference between like other recent trials for using noncalcified plaque volume. We specified...

On this trial had fairly low plaque...

High level of plaque at baseline, which is right in line with our expectations. But speaking of the cardiologists now, the whole field in cardiology is changing to look at these imaging modalities clearly heart flow now by Caristo. So the future really is changing plaque before you get to events. And remember, we think is going to be a landmark trial because I think we'll be the first out there to show a benefit for LDL lowering, especially with the combo.

I think we're ahead of VictORIA, we're the lead on that study. And then cardiologists love this imaging like the Halton trial that Amgen had. It's not in their label, but they promote it with their reps, and it's very well received by cardiologists, and it's a big -- they would have thought it was one of -- before REesLIus, it was one of the big drivers of growth was having an imaging study showing a regression of plaque. And so we think that's going to be a great value add for Obi with having the membrane study in our label or in promoted as well.

They like images.

Yes, right. We like seeing things getting better.

I have 2 questions for you. Can you share some insights from your discussions with the FDA the SPINOZA trial. Do you think that p-Tau can potentially be in the future label for OV? And what will the time lines be for this trial?

We had -- the protocol was reviewed by the FDA, gave us. What they -- not getting too far ahead of the design because we want to come out with a big splash on this. But they do like p-Tau. They're not quite ready to approve a drug based on p-Tau. But as John said, we're getting there, a lot of advocacy going on among especially the APOE4 patient community, but they fine with it being an endpoint. We are doing cognition as well in the SPINOZA trial.

But the -- the point is that we haven't -- we don't think approval can be based on SPINOZA, but we do think it will lead to a very important follow-up study. And I mentioned this message about we have very good data on -- if you have high p-Tau in your E4, your progression from normal to mild cognitive impairment is 15% to 25% over 5 years. That's better than a MACEE. And so we can actually do a reasonable study within 5 years to show prevention of Alzheimer's -- thing -- they already have Alzheimer's disease, just to keep that clear.

They already have Alzheimer's disease, prevent the conversion of normal to abnormal in a reasonable period of time and a reasonable cost. But the FDA has approved the study and -- but they want to see the spectrum of risk patients in that study. We'll announce that in the relative near term when we start the trial officially.

Maybe one more question for BJ. Next year with LLC lowering in MACE benefit, are there any other factors that you think will be important for an update? And what do you think you'll get into?

So yes, in terms of the items around residual risk that we talked about, right? Those are all -- we think are actually very important. Michael and John specifically have spoken about Lp(a). Again, small particles, the rate of new onset diabetes, each of those things have been reflected even in our demand study in terms of importance for prescribers. So there's a relative input in that. In terms of whether we think they'll get in our label or not, I actually don't want to comment on the probability of that. Let's just say we're doing everything we can to include as much as possible in the label or -- and create data that allows us to be consistent with the label.

Yes, I just want to add that the AI world is changing everything dramatically. label, not label, I think that's going to -- I really don't think it's going to matter that much pretty soon. because doctors are going to use AI to determine what the right drug is for a particular patient. And the more we -- that's why we're a publication engine where we want to generate all these papers that gets into the AI sphere, so they can generate data.

And the more we can do that, the more we're going to get the information out there for clinicians because it's a changing world. It's changing very rapidly. And I don't -- and the gene is out of the bottle already when it comes to how doctors are using AI for getting their information. So it's going to change everything that we do. We already -- we hired a full-time AI person about a year ago, which has been a great -- helped a lot with PREVAIL assessment and even how design SPINOZA, how we design trials, how we go about looking at our data, a tremendous benefit already.

But I think a lot more to come when it comes to how we launch the drug and how we communicate information to clinicians and to patients. So we're going to see a huge difference in just a few years about how information is circulated to all our stakeholders. And we're trying to be cutting edge on that as well.

Yanan from Wells Fargo. A question on the MACE-3. I think you mentioned if PREVAIL replicates or show a similar MACE-3 as BRAWY, you should be okay for the interim, right? But I was wondering, could you remind us the MACE-3 benefit and the definition of the MACE-3 from BRADWAY because there could be some changes between the MACE-3.

MACE-3 was in the right direction. We had -- we didn't -- it wasn't the same magnitude because of stroke in the wrong direction. So again, 1 year is not the right thing for MACE-3. But what we're saying is we have -- what we have about MACE-3 across all the trials is that we have -- MACE3 is the easiest one to compare across trials. So it's nonfatal MI it's death, CHD death or CV death and stroke, okay? So those are easy -- relatively easy to compare across trials. So what we're saying for MACE-3 and for esoph, we want to see this the MACE-3 being the same type of reduction that we saw in MACE-4 in BROADWAY, I'm trying to say. That's the point I was trying to make. In other words, that 21% if we're -- we have -- as I try to say to -- we have some wiggle room there, too. It's not -- it doesn't have to be 21%. It could be less than that.

We're not going to see how far less. But we have some room to move on the MACE-3 as far as our powering is concerned right now. But what we've said already publicly too is that the event rates are down, so we're imputing a certain placebo rate that we can carry forward from BROADWAY even with Day into the blinded MACE-3 event rates, and we're encouraged by what we're seeing. I mean, so again, we can't use the BROADWAY 1-year MACE-3 data. That doesn't help us. But other than the event rate itself, the MACE event rate in BROADWAY, we carry that forward year after year, year 2 now, we're getting close to -- we're in year 3 now. So we see how the events are tracking down and we can make assessments about when we have the interim analysis with the number of events that we have, our MACE-3 total, we impute a certain placebo rate, we it looks encouraging is what I'm trying to say.

I think what's very important when you guys write about events is that you imagine how it goes these days. So you're in a city like this, you get chest pain. So you call 911, you're rushed into an ambulance, then door-to-balloon time is like 2.5 to 4.5 hours, you get a stent, you prevent a nonfatal MI and you prevent a fatal MI. So that's the first event that occurs. So if you look at the time line in trials in BROADWAY, by far, the first thing that happens is you prevent PCIs because that's the first thing where your therapy has an effect on. It takes longer to prevent nonfatal MIs, even a little longer to prevent fatal MIs, that's later and even longer than strokes because stroke arteries are like 3x bigger than coronary arteries. So for lipid lowering to have an effect on the stroke artery simply takes longer time.

And so when you understand that, that's the sequence of events, you also understand that if you look at 4-point MACE in a 1-year trial, you are going to be positive because the vast number of events that you prevent are PCIs. If you look at 2 years, you have an effect on all the events, the smallest effect on stroke. But actually, if you go over the 2 years, everything catches up. And then generally speaking, 4-point MACE is at its peak and 3-point MACE is actually getting close to it. And actually very often these days now, the effect, the potential effect on 3-point MACE is better than on 4-point MACE.

Look at Fzalus, 19 versus 23, I think, or 24 or something. And so that's the reality of the new. In the old days, -- you had chest pain on Monday. You went to your cardiologist on Friday, the chest pain was gone. He thinks, well, let me give you a stent Anyway, it's good for my wallet. So I'll give you a stent. That didn't prevent any heart attacks. So practice has really dramatically changed. That old thing -- I mean, in Europe, there is no reimbursement anymore for a stent that is not what's called ischemia driven. So patients do need some sort of complaint before the insurance companies pay you for a stent. So that's...

Yes. Great. That's super helpful. I just wanted to clarify, it sounds like the alpha at an interim is 0.01. Is that like the sum of the 2 MACE-3 and MACE 4? Or how do you think about the interim?

There is -- that is for MACE 4 or MACE-3, we have a different p-value requirement. We are not saying what it is, but we have a different p-value requirement for MACE-3, -- not as -- again, it's a secondary endpoint. We don't have to be 0.01 for the secondary endpoints...

Matt, do you want to say...

All right. I think that's all we have time for on the questions. Obviously, the team will be around for a few minutes more. We also have lunch available for people in person. I want to thank everyone for coming today. And I guess, Michael, any final comments?

Again, for coming. We're happy to keep engaging with everybody over lunch or socially here. So please stay around. I think we have lunch right outside. Okay. Perfect. Okay. Thanks, everybody. Thank you.

NewAmsterdam, very pleased to have -- Michael, welcome -- can I give you the opportunity to maybe just level set us and make some opening framing remarks on the company.

Sure. Thanks. Thanks, everyone, for being here. We've had a really productive year firing on all cylinders. I mean our -- all our trials are rolling along on schedule or ahead of schedule. Of course, the most important being PREVAIL, which is our 9,500 patient outcome study, and I think we announced just a few months ago that we're going to do an interim analysis based on a number of factors, we can go into more detail, but that interim-analysis -- we'll start the actual point at the end of this year, the readout will be in the first quarter of next year.

Well, that's, I guess, one of the most -- that's a great segue into what I think is probably going to take a lot of the discussion, the PREVAIL trial, given how important it is. I want to just maybe double-click a little bit more on the interim analysis. I think just first is on timing. You said it's going to be done by the end of the year with the results in the first quarter...

Well, you said event rate time point, which is going to be the end of this year approximately. And then it takes time to adjudicate all those events and go to -- growth before the DSMB, and then they have a charter, which they -- guides them on whether we hit the criteria for stopping the trial at that point?

So walk us through, Michael, the decision to introduce this interim right now? And I know you guys have talked quite a bit about it, but I just would love to just hear the framing again, how did you weigh getting to market potentially a year earlier versus the risk of potentially also jeopardizing the trial?

Right, right. We're not jeopardizing the trial in any way. In fact, just to go back to the -- it's really important to go through the history of PREVAIL. When we started the trial, we also started our Phase III LDL trials at the same time. So BROOKLYN, BROADWAY, TANDEM and PREVAIL all start at the same time. So -- and basically, we didn't have the funding to finish them all, especially PREVAIL. So we were a private company. And our plan was to get our Phase III readouts and then raise more money to finish the trials accordingly.

So we went public, we raised the money. BROADWAY worked out well, but we purposely designed BROADWAY to be a mini PREVAIL. And in fact, for the first time, and a lot of companies have copied us since is that we made the Phase III trials very heavily weighted to BROADWAY on numbers. So 2,500 patients in a single trial, all at high risk to give us a large number of events in a single trial in Phase III LDL that we were hoping would provide a lot of support for PREVAIL working. It was designed as a mini PREVAIL.

And so it all worked out very well in that regard. We had 2,500 patients. We had a large number of events, again, larger than any other Phase III lipid trial done to date over -- well over 100 events at 1 year. And we saw this 21% relative risk reduction of our new 4-point MACE.

We've also had decided that BROADWAY would be informative on the final design of PREVAIL because we had initial 4-point MACE that a lot of companies had used, which was urgent revasc cardiovascular death, nonfatal MI and total stroke, and that's used. In fact, Horizon is using, I think, the similar. We powered it for 20% relative risk reduction. So roughly 1,000 events, 1,000 events, 20% relative risk reduction.

Once we had BROADWAY, and we looked at the event rates and we saw that the 4-point MACE that was now being used more -- in more recent trials, like CLEAR Outcomes, FOURIER and so forth. It's also the CTTC definition of 4-point MACE that's being used for all the meta-analysis of all the LDL trials. We came -- that was also where the 0.79 hazard ratio was present. So we made the decision, we announced that a year ago that we're going change our 4-point MACE to that 4-point MACE. So that -- so BROADWAY is very informative on letting us know that, that was the 4-point MACE that was recognized as now the new appropriate 4-point MACE for the recent trials, and it was also our best hazard ratio in the BROADWAY data. Again, all the events were in the right direction except for stroke. But so that provided the best benefit for us in the BROADWAY trial.

So with the very large number of events and the 4-point MACE rate, we decided -- we raised a lot of money. And now we had enough money to go longer to make sure that we powered the study not for 20% relative risk production, but now 15% relative risk reduction. So with that in mind that we would now want to go to 15% relative risk reduction power because keep in mind that all the recent LDL trials range from 9% to 15% on their primary endpoint, 4-point MACE.

Ezetimibe being 9% and Repatha and alirocumab and evolocumab, Repatha and Praluent at 15%. So we felt that 15% be powered with strength of the trial significantly. But with that requirement to go to 15% power, we knew because we were limited by patient numbers were already fully enrolled. We have to go longer.

So we're going to go longer. We also have more events now because the 4-point MACE that included total [ revascularization urgent ] also gave us about 20% more events. So we put in the new event rates, the new 4-point MACE, that gave us more events. But now we decided to go longer to power the study to 15% relative risk reduction. In the meantime, we're tracking our blended event rates, and we're seeing that the blended event rates are much lower than expected using, again, BROADWAY as our benchmark of what the event rate should be, because again, BROADWAY and PREVAIL have the same patient population, the same DSMB, the same adjudication committee, many of the same sites. So if any study could tell you what your placebo rate would be and your outgoing outcome study would be BROADWAY.

So BROADWAY should be a really good, strong predictor of what would happen in PREVAIL. So knowing the event rates in BROADWAY and knowing they have very similar trials, we can make predictions about what the event rate should be in PREVAIL. And we're seeing lower-than-expected event rates, which is consistent with that 21% relative risk reduction. So if that's the case, then an interim analysis at that point that we designated would give us enough power to stop the trial with our -- with the P values that we selected, which are important for regulatory approval for both 3-point and 4-point MACE, and that would get us back on track for that timing of approved -- finishing the trial in the first quarter of '27. That's a long answer to your question.

No, it's actually a great answer because I want to stay with event rates, believe it or not, for a second, because you've stated that the blinded event rates are dropping in 2 and 3, even more than the expected placebo decay. So I guess what gives you confidence that this is being driven by obicetrapib's benefit rather than the placebo arm outperformance -- or changes in the standard of care. So -- and maybe also just while we're on that thread, talk about some of the analytics you did with other studies that helped lead to that decision. You touched on this a bit, but let's keep going.

Yes. So like I said, we looked at the first year event rates with PREVAIL and they matched almost exactly the BROADWAY 1-year event rates across the board, 3-point MACE, 4-point MACE, death, nonfatal MI, all the events, all the composite events match very closely to PREVAIL. So we felt that, again, the way it was an excellent kind of guide to what would happen.

Now historically, what happens with placebo event rates across 14 different trials. We know there is a decay, but this was greater than expected decline in event rates more than expect from a decay over these multiple trials. And again, 14 trials, we can measure to predicted decay. And like the famous line for us at least, is a good way to lower your risk of heart disease to be a placebo in a cardiovascular outcome trial. I mean, so that's the -- obviously, that's an issue that we were -- we know about and we're aware of.

But even with that in mind, we're seeing this decline in event rates going forward that would be more than expected and consistent with that, what we saw in the BROADWAY relative hazard ratio benefit. And so that gives us, again, confidence on that -- BROADWAY does accurately predict PREVAIL and that this decay that we're seeing is more than expected from all the other trials that have been out there. We're not seeing -- we've been very carefully monitoring drop-in, dropouts, add on GLP-1s or SGLT2s or PCSK9s, and we're seeing very low single-digit drop-ins to any of these that would affect the event rates. And so in that sense, again, we feel the most likely explanation is that obicetrapib is validating the 21% relative risk reduction we saw in the BROADWAY study itself.

We also looked at 14 different trials for all CVOTs of recent vintage. And again, we know the decay rates, we also know that our event rates even when you -- especially when you adjust for our risk because we designed PREVAIL to be a high-risk population, high LDLs over 100. All patients have ASCVD, 50% have diabetes. So you look at SELECT, for example, LDL was [Technical Difficulty] 80s and the event rates, and we know were lower than [Technical Difficulty] you look at other trials that are done in a contemporary time, that's relatively recent. We're seeing event rates that are lower than those annualized event rates in PREVAIL.

So again, we feel that this interim analysis gave us a 2 shots on goal approach that we -- at the end of the day, we made the study a lot more highly powered for 15%. That's our primary objective. We don't want the study to fail the drug. So we knew that would take an extra year, even though we modified the 4-point MACE because even rates are slowing down. But this lower event rate is giving us, again, encouragement that the interim could stop early the trial and give us a chance to be on the market 1-year ahead of schedule.

And then maybe on the MACE endpoint change, the 4-point MACE, you changed the 4-point MACE definition from urgent revascularization to total revascularization or CTTC definition, which adds roughly 20% to 24% more events. I guess why was that change made? Talk a little bit about that? And how does requiring MACE-3 as well as MACE-4 at the interim affect the likelihood of an early stop.

Right, right. Well, so again, the 4-point MACE was driven by 2 reasons. One is BROADWAY, it was as good as urgent and elective for the same hazard ratio. Again, clear outcomes and facilities are all both using total revasc. They saw no difference in urgent versus total. And so that to us is kind of a simple reason to go with the total revasc as opposed to urgent. So that made a lot of sense. And so -- and then again, the CTTC definition also using -- also REVEAL, which is the anacetrapib trial, used total revasc. So that gave us again a guidance there on that. That test was a pretty easy decision. And also just keep in mind that the big studies recently done, both one's called COURAGE, one's called ischemia and my field is a cardiologist, they both showed that using medical management versus a stent, there was no outcome benefit.

So the care has changed in the last several years where revasc is becoming much more evidence-based decisions like -- instead of seeing a lesion and dilating it, there's -- you got to have symptoms, you have to have new onset of symptoms or symptoms that are getting more severe before you get a stent put in, even payers are demanding more validation of medical necessity. So the blurring between elective and urgent is much less than it used to be 10 years ago.

And then I guess on the MACE-3 requirement, why is hitting MACE-3 a requirement to stop at the interim but not strictly for the final analysis? And how much of a second year event decline is coming from the 3-point components, which is nonfatal MI, stroke, CV death.

So it's actually really good. That is our own -- again, our own conservative thinking on the 3-point has to hit also because even though the primary endpoint is 4-point MACE, in Europe, in particular, regulators like to see 3-point MACE positive. So we would hate to have a situation where the -- the 4-point hit and the 3-point did not and that would -- and so we don't want -- that's our secondary endpoint. And there are a lot of academic schools of thought, even the FDA itself, they've never been an example where this has happened, but if you hit on 4-point, but did not hit on 3-point, then your -- the regulatory certainty is in question. So you want to hit on both. And so we felt that if we're not going to -- if we're going do an interim analysis, it would be easier not to have 3-point in there to stop the trial. But for us, that would be an unfortunate situation, if 4-point hit and 3-point did not. So we want to make sure 3-point hits as well.

Now the threshold for 3-point hitting is not as much as the 4-point because it is the secondary endpoint, but it's still a very significant p-value to get to stop the trial. So that part is -- it's more of a -- we don't want the study to fail the trial. So if we could have gone a year longer and hit the 3-point and we stopped for that reason, we would have regretted that decision. So we want to make sure that both 4-point and 3-point hit at the interim to stop the trial.

Very clear. Let's maybe start bridging into the commercial opportunity. We've spent a lot of time on the trial. But I guess regarding the ultimate MACE level benefit achieved, you've stated that it doesn't really matter what the ultimate benefit is, whether it's 10%, 15%, 20%, why would you believe that to be true from a commercial perspective?

Well, that's just what the -- all the data tells us -- 1 thing I want to make also a point I forgot -- you asked about it was the 3-point MACE reduction that we're seeing in -- we're seeing all events going down, but in particular, the 3-point MACE. And then that's giving, again, encouragement on the whole thing.

Now regarding the commercial benefit of 20% versus 15%, we really don't see that driving uptake that much. I mean, it has some impact. But most clinicians, there is -- and based on our surveys, there's 10% of physicians who care about what the percent MACE benefit is. But yet, most doctors, all they want to know is the study is positive or not. All guidelines want to know as the study is positive or not. Like for example, the new guideline just came out, they rank Repatha, Praluent and bempedoic acid, Nexletol as the drugs that go to because they have outcome benefits. They don't talk about the relative risk reduction of those drugs. So this have evidence base of benefit. So for most doctors, they don't even know. In fact, when you ask them actually what was the relative risk reduction, 90-plus percent get it wrong. I mean they don't know what it is. So it doesn't affect utilization as much as you think it would.

Another example is Wegovy, has select 20% relative risk reduction. Tirzepatide has no benefit on outcomes. People are using tirzepatide a lot more than Wegovy. So it's just an example of -- these outcome studies, I get in the academic world, they're -- what they are is potentially important. But in the real world, it doesn't matter that much. I mean -- and so we feel that the biggest reason why commercial uptake would be -- will go gangbusters with obicetrapib is because the LDL plus first positive benefit on outcome. That's all -- that checks the box. But the Lp(a) lowering, the diabetes reduction, small particles, the Alzheimer's benefit in BROADWAY that we saw, that's going to really drive uptake and our data shows that strongly that we get increased uptake for those other LDL-plus benefits beyond -- compared to other LDL drugs, including the oral PCSK9 in the market.

And that's a great segue, Michael, just talking about just the commercial landscape or even the competitive landscape, if you will, right? You've got the Merck oral PCSK9 launch potentially before the end of this year. Enlicitide, you've got AstraZeneca's oral PCSK9 combo strategies across their CVRM portfolio. You framed sort of these entrants as wind in our sails rather than competitive threats. What evidence supports the market doubling beyond the 30 million patients not at goal?

Well, now the number is a lot bigger because of the new guidelines. It went down to 55 million. So it's a much bigger number. That really makes a huge difference on the numbers. It's probably -- it could be as much as double that. And so lower is better is the key, especially Lp(a) lowering if that is validated. And Horizon doesn't have to be positive in its own right. It could be something that's in between, which could even be better for us. And it's something that showed a benefit that's more enhanced when you have an on-treatment analysis or things like that. I mean Horizon has -- it's on the border line of where it's going to achieve statistical significance based on the powering and so forth. Again, they powered it for 20%.

I mean -- so again, we want to -- but the -- when you have a drug that lowers Lp(a) more than the oral PCSK9, you have a drug that reduces risk of diabetes, not increase the risk, which is in the labels for the PCSK9 inhibitors to some degree, even though I don't think it's a real issue.

The diabetes and the Alzheimer's benefit, we think the Alzheimer's benefit is getting a lot of traction with all the KOLs out there because they know that ApoE4 is a lipid gene and the prevention data with p-tau217 -- the strengthening of the benefit of p-tau217 being highly correlated with amyloid on PET and that's highly correlated with progression to Alzheimer's. That's a great message. We're going to validate that with an upcoming study called SPINOZA, and we're going to validate that.

So I think all that together gives you a highly motivated reasons to use obicetrapib over any other Lp(a) drug. And of course, the biggest issue in my mind is the safety and tolerability, ease of use that really drives wide utilization, especially by primary care doctors. And primary doctors love ezetimibe before the whole enhanced issue blew up, the benefit. Now it's -- now it's growing again. It's going gangbusters. But what was easy about ezetimibe was it was so well tolerated and safe, even though 15% LDL lowering wasn't -- but they rather get something that's very well tolerated and safe as opposed to anything that has any side effects or has challenging use. And so we feel that's where obicetrapib really excels in that regard.

And then I guess on the regulatory strategy and the filing time line you filed in Europe, which I want to talk about. I guess just maybe just staying with that, what are the updated time lines in that region?

So yes, we filed in Europe. We should have approval this year for Germany and the U.K. Everything is going well on the regulatory side there. And then we'll be launching across Europe with our partner, Menarini across many of these different countries.

And I guess because you're in the situation where your partner in Europe is going to be launching a drug before you launch in the U.S. So explain to us in the world of MFN, how does that affect the pricing architecture as you launch in all of these different markets in Europe?

Well, I don't want to comment specifically, but we are working close with Menarini on how best to go about the commercialization pricing strategy. But we've got Steve Albers, who ran access at Novo Nordisk as our access public affairs lead, and he's a fantastic expert in this area. What we're working with Menarini on there are ways to structure pricing that gets us closer to the U.S. pricing.

Across the range of countries?

Well, it depends on the country, of course. And you remember, there's a very complicated system in Europe. But there are commercialization agreements. There is -- there are confidential pricing. So Europe is trying to adapt to the MFN world. But by the way, we hear recently, and you may know as well, if not better than us, but we feel that anything law-wise, codification is unlikely to happen.

On MFN.

On MFN, yes.

So the industry is very opposed to it.

Right. So...

Also you're saying this could just -- even if there is something that emerges out of that, this is something that could eventually expire in 3 years...

Or just we feel that. We have a lot of good arguments. It's not our -- we have no control over pricing in Europe. We have arguments that we can make about why that wouldn't affect us. But nevertheless, we are working closely with Menarini on how best to approach the pricing in Europe.

Okay. And then maybe on the U.S. side, Michael, can you file the U.S. application ahead of the interim readout? Is that -- I think that's the strategy here...

We potentially, we're talking with the FDA and we're actually -- we're blessed at the FDA with the same team we've had for 5 years.

And how are those discussions going?

They're going well. I mean so we both have the same objective, which is that we want to see the drug on the market with outcome data already in hand. And so they -- we both have the same objective that we want that. They want that. So we're working together on how best and how to time that effectively.

Okay. Let's talk a little bit about Lp(a) and Horizon. You touched on this briefly, Michael, you and I've had some conversations about this in the past, you've described obicetrapib is serving the 50 to 150 Lp(a) range without competing with injectables relegated to the higher-risk established disease patients. So I guess how do the various Horizon outcomes, success, a near-miss, a failure, each play out for NewAmsterdam?

I think a total miss is unlikely because it did -- it has 2 interims, yes. So let's assume it's the next scenario, which is that it doesn't reach the p-value on the primary endpoint that people are hoping for, which if it's not -- it's not 20% or greater, it may not be statistically significant. It might be a P-value that's below -- not below 0.05, let's put them that way. Again, I think that's a scenario.

But there are other scenarios where then it becomes, okay, let's look about the study itself. I mean there could be relatively high dropouts. It is an ASO. It has a lot of skin reactions. And we've -- so let's say -- once you look at on treatment or those that took the drug, it become significant.

We can look at how much Lp(a) you got and then model that for benefit. So there are ways that the study, even though may not be successful as a regulatory approval, trial could give us validation at Lp(a) has a benefit. So that would be a best-case scenario for us in our situate -- I hope not -- I hope it's a positive trial. As a clinician, I can tell you in my lipid clinic, I see patients 4 days a month at University of Chicago, I would say 3/4 of them are high Lp(a) patients throughout -- want something to take for their Lp(a), their bad family histories, they're worried about it. So I think it would be most important to get this drug out there as soon as possible for those patients.

With that said, though, it will be relegated to those that have Lp(a) above roughly 150 nanomoles per liter in our existing heart disease. So it would not be available for those below 150, we still have high risk down to 50, and/or they don't get a heart disease. And so it's also going to be very expensive, I believe, they'll be pricing it pretty high in that biologic range probably.

Because it's -- that's how they design the high-risk group to get the high absolute benefit for the trial. And so we become the first Lp(a) lowering drug out there not technically by indication, but by benefit that people will be aware of that lowers Lp(a) in that 50 to 150 range, quite effectively by about 50%. So statins, unfortunately, they do help, they lower LDL, which makes a difference, but they don't lower -- they actually raise Lp(a). So obicetrapib becomes the really go-to drug for anybody with high Lp(a) in those that 50 to 150 which represents the majority of patients that have Lp(a) out there. So we see high Lp(a) [Technical Difficulty] official as a real upside for us in the marketplace.

Okay. Maybe in the last couple of minutes, let's talk about Alzheimer's. Michael, you plan to announce a new Phase IIb at the July AAIC meeting?

It could be August, early August, yes.

Okay. So presenting 4 new studies based on BROADWAY biomarker data...

No, no, no, you're right. We are presenting 4 posters at the meeting. Our Investor Day is in early August, obviously, we're announcing the SPINOZA trial. Okay, I'm sorry.

Okay. Yes, we are -- we have 4 studies. So I guess talk to us about the design, the target population, time line and how could early intervention expand...

So a great question. I think -- so we use a lot of AI technology in our data. We have a very rich data set. We have 1,500-plus patients on obicetrapib for a year. And so we already announced that in the ApoE4 patients, especially the [ 4/4 ] homozygous, we got a benefit across the board on p-tau217 and also on other biomarkers. NfL, GFAP, Ptau 181, amyloid, all the biomarkers improved in the homozygous patients significantly, which was kind of unprecedented, especially NfL, which doesn't seem to be benefited by the anti-amyloid therapies.

So that was quite exciting. But then using AI technology, we found that we have enriched the study for those that have a mildly elevated p-tau217 and have either 4/4, 3/4, even 3/3 that are older, they also benefit from obicetrapib. So if you think about Alzheimer's, 4/4s get it in their 70s, 3/4 get it in their 80s and 3/3 is getting their 90s. So in our study, we found that all 4/4s benefited. So we think starting at age 55 is a good starting point. For 3/4, 60, 65, they start benefiting. And then over 75 for 3/3, they start benefiting.

So we think we found -- again, it makes a lot of biologic sense that we're trying to treat 20 years before there's cognitive impairment symptoms. Then we found that obicetrapib was benefiting these patients based on those risk markers and using Ptau as a great biomarker for amyloid in the brain that we're seeing this prevention of amyloid accumulation over that 12 months quite significantly across those 3 types of patient populations.

So we're studying -- we've been doing a 3-cohort 400-patient trial with those 3 cohorts, 4/4s, 3/4s and 3/3s, having those other enrichment criteria to show what we can do in a prevention model for Alzheimer's. Again, where we're really benefited by the fact that the p-tau217 keeps getting validated over and over again as an excellent biomarker for both prediction of progression and benefit in the trials, but also that the disease is being redefined now. Everyone's -- Alzheimer's used to say, that was dementia. Now they realize Alzheimer's is targeting 20 years ahead of any cognitive impairment. So they want to start treating Alzheimer's 20 years earlier now. And we hope that makes a big difference. And if you're in the lipid world like I am, we realized if we -- we use the LDL lowering to treat heart failure, we never would have succeeded with LDL lowering, we had to treat LDL lowering before there was heart damage to get the greatest benefit.

We're certainly looking forward to seeing how those trials progress. Best of luck to you, Michael. Thank you so much for being with us. A very comprehensive discussion. Really appreciate it.

Thank you.

Bank of America Healthcare Conference in extremely toasty Las Vegas. Ending up our final talk of the day is I'm very pleased to have join us the team from NewAmsterdam. So this is Ian Somaiya and BJ Jones, Chief Commercial Officer. Gentlemen, thank you so much for joining us.

Pleasure.

Yes. Thanks for the invite.

Maybe just to start at a high level for those maybe not as familiar with the NewAmsterdam story. Can you give us a brief overview of the company and obicetrapib?

Sure. Look, it's been an exciting couple of years. Obviously, we've shared a lot of data with you from our Phase III studies for both of our lead programs, obicetrapib as well as the combination with ezetimibe. And really, the goal is to help redefine how patients with elevated LDL are being treated today. The data from the Phase III studies has been quite consistent with the monotherapy showing somewhere between a 35% and 40% reduction in LDL. The combination that would benefit that's in the 50% range. And the benefit goes beyond LDL. So that's when I said the opportunities to redefine the care of patients is looking at the LDL plus characteristics of the drug. So it's the roughly 50% reduction in Lp(a). It's the improvements that are driven by the HDL raising profile of the drug, which include the reduction in the rate of new on-set diabetes, the improvement in kidney function that we recently reported at the ACC as well as the early Alzheimer's signal, which we're going to be further exploring in a short order in a Phase IIb study.

So that gives you a sense for kind of what we've shared over the past 2 years. More recently, and specifically last week, we provided an update on our outcome study where based on an evaluation of the blinded data, what we're continuing to see from now up through the 2-year mark is a continued decrease in the overall event rate, which is obviously quite encouraging. Although the data remains blinded, the comparisons we can make are to our BROADWAY study, which was nearly identical in design and was conducted at the same time, the first 2.5 years of BROADWAY, the same 2.5 years of PREVAIL.

And given the overlapping patient populations, it makes for a very unique basis for comparison. So the fact that the 1-year data of PREVAIL on a blinded basis look comparable or in line with what we saw in BROADWAY and now observing the 2-year mark where the trends are -- continue to be quite encouraging, what we decided to do and we announced this last week was introduce an interim analysis, which will be triggered by the end of this year and the results shared in the first quarter of next year, where we feel good about the potential for that trial, for the interim to lead to the trial concluding. But if we're wrong and the trial needs to continue, then we're looking at an extension that goes into the end of next year. So overall, we think we have 2 opportunities to deliver on what we expect to be a positive PREVAIL outcome and that ultimately unlocking the -- what we expect to be a blockbuster opportunity for the drug.

Lot to pick apart there. But maybe let's just start with, is there one output that's truly differentiating between ApoB, Lp(a), LDL particles? Or is it just the overall breadth of what you can lower there?

Do you want to speak to that from a commercialization standpoint?

Sure, I'm happy to. The first thing we need to do, and we've done effectively is just make sure is can we actually address what is the primary like metric in some sense, right? And that's what's the efficacy associated with LDL. And we feel very confident in that regard, Ian just walked through that data for you. So we can say that we are consistent and kind of best-in-class in terms of efficacy around LDL. We can also say that we're best-in-class as it relates to safety and tolerability. We're an oral, obviously, we're in a space in which we're not SNAC technology. We don't have to worry about like eating and issues of that sort. So it's a very different profile than what's either currently on market or coming to market. But the relative benefit that we also see across Lp(a) and diabetes and small particles.

And as Ian also mentioned, the hope and what we see kind of initial in terms of Alzheimer's and ApoE4 folks. I wouldn't say it's any one particular incremental benefit. It's the host of those benefits because what we're doing essentially is like reducing what is the overall risk. And so again, with all the primary research we've done with over 1,000 doctors over years now, and basically shown RTPP versus others currently on market or coming. Others will do well. It's a massive market and there's tremendous unmet need, but consistently, it shows that OB, OBEZ will do better than those competitors.

You opened up a great question. How many patients don't currently achieve their LDL-C goals? To what extent is this going to be structural versus the pharmacological? And then when you think about how can an asset like obicetrapib both capture and grow share?

Well, I'd say -- yes, is that when we look at essentially kind of what's happening in the marketplace today, sadly, frankly, a tremendous number of patients are actually just not meeting goal. And they start on statins, and they do well, but not well enough. And so what we found is that even current data basically says there are about 30 million of those folks who are actually not achieving what is their base goal and the target. And now that target is shifting, going to be more difficult to get to, if you will, because of the guidelines, the evolution of guidelines, which is very good for clinicians and for patients to get people actually where they need to be. And so again, we're talking about tens of millions of folks who are kind of in that sweet spot of where we would be used in addition to the statin.

And I would say that, again, it's -- there's -- you asked the question around is it structural in some sense. It's just a means of people actually, whether they be specialists, but especially in primary care is that today, there's this apathy, not only on the clinician side, but the patient side as well in terms of if I just put somebody on a statin is good enough. right? Like I've done my job. And the hope is that in the very near term, we start to see a more aggressive nature in terms of prescribing and really looking to achieve the goals that are necessary to get to the outcomes we're looking for to reduce this overall tremendous burden in CV.

And the most important data set that we've seen to drive home that point is Amgen study VESALIUS, where in this patient population, the benefit that you can provide by effectively managing LDL in terms of reducing overall risk became quite clear. So there was a 19% improvement in their MACE-4 number, 25% when it came to MACE-3, and those are the hard endpoints. And for the first time with that drug, we saw a mortality benefit. So they addressed one of their biggest criticisms from their secondary prevention trial.

So there's obviously the guideline changes that BJ spoke to, but there's clear clinical evidence. And this is the way Europe has been treating patients forever. So it's the opportunity for the U.S. to catch up. And that 30 million patient number, we don't know what -- where that number goes. We could easily be looking at an opportunity that's twice as large as what we had only a couple of months ago. And that's why really every company, every drug has the opportunity to benefit. And as long as we focus on driving that point home, manage your LDL, get the patients to goal, all options available to them will get utilized.

Maybe we could drill down a little bit deeper into this, Ian. Obviously, you have the expanded use of the parenteral PCSK9s in first-line setting, but now the orals as well. Is that a risk at all to obi?

Look, I learn a lot from BJ. And obviously, those are -- these are all commercial [indiscernible] questions. So I want to make sure that he has an opportunity to give his answer.

No, absolutely. And we actually don't see this as a risk in some sense at all. Frankly, as we've said, the market is just so large, it's a tremendous unmet need is that it's a good thing for doctors to actually have options and patients have options as well. And so what we see in the near term is tremendous increase in terms of overall utilization of branded meds in this space. And even ezetimibe, right, is growing at 20% year-on-year. And in the branded space, driven primarily by Repatha is growing at 40% plus. And so we expect that to continue.

We look forward to what is the Merck launch in the near term oral PCSK9. They're going to continue to fuel, right, and promote branded but also unbranded, right, to get to patients to activate, right. And that's all positive. And frankly, honestly, it's wind in our sails because when we enter the marketplace, the market will be much bigger and doctors and patients' behavior will be changing as well, where they're looking now to address this in a more aggressive way. We come to the marketplace with actually a better opportunity that can not only address LDL, but also the incremental benefits we talked about. So we look forward to that.

So in order to demonstrate the superiority, can you maybe give us a sense of BROOKLYN, BROADWAY, TANDEM, incremental insights that you provided at ACC just recently. I mean, what stands out in terms of efficacy and differentiation? And how do the data position obi relative to these other approaches?

So just from a clinical perspective, if you look at data, whether it's the drugs that are on the market today or the drugs that are in development, the benefit is primarily limited to reduction of LDL, which is obviously very important. But the risk that these patients experience goes well beyond that. So as you look at the other populations where risk remains, it's the Lp(a) aspect of it. And obviously, at some point this year, we'll get data from HORIZON, and there are other trials that will follow. And we'll have an answer to the question, how much risk is there with Lp(a). And when you look at the available options today and the ones in development, we have a pretty dramatic effect on that risk factor.

As you think about the LDL particles, CETP is central to the production of small particles. And what we've seen in our data set is complete elimination of those small particles. So as we focus on residual risk, with a patient that's on a statin or combination of a statin or other drugs, this is one aspect, one key aspect of it, which differentiates us from other molecules. And the same is true for diabetes. Diabetes is a risk factor, and that's something that we -- not only us in terms of obicetrapib in our Phase III data, but really the CETP class has consistently shown roughly a 15% reduction in the rate of new on-set diabetes and related endpoints.

So this is yet another point of differentiation. When you look at statins, the higher the dose of statins, the greater the risk of diabetes. And if you're on the highest dose of statins, your risk increases by roughly 35%. So there is an opportunity for us to be combined with a statin. Potentially bring the dose down of that statin and still get the patient to goal. So if we look at the combination data, this is the combination of ezetimibe and the TANDEM study results, we're able to get vast majority of patients to goal, even the new goal, the revised goal of 55 milligrams per deciliter. So we think this is an ideal product and the timing couldn't be better.

And we spoke to the guideline changes. But when you look at the labels, the labels have all been harmonized now. If you have a successful outcome study, what you inherit is a label for treatment of all patients with elevated LDL. Your MACE benefit is no longer limited to the individual components of MACE where you hit stat sig, you get the full benefit and the label claim for that. So it's the harmonization of labels, it's the treatment guidelines. It's the resetting of the price many years ago, which brought -- which has opened up payer access and the benefit of having multiple companies saying the same thing, which is get patients LDL under control.

So with that in mind, then why wait for PREVAIL before filing? Again, if LDL-C is recognized as a validated surrogate for CV risk, how necessary is kind of that stand-alone outcomes?

Yes. So we still operate within IRA. So that's the big consideration for all of us as we contemplate launches in the U.S. And based on the market research BJ and his team have done, what's quite clear is that if we deliver on positive outcomes data, and it's either sort of a yes or no, right? As long as we have the data, we get the broad label and we get the broad payer access. So that's what's limiting or informing the timing of the filing and approval in the U.S.

Last one from me. Obviously, a few days ago at your earnings, you provided an early update on PREVAIL. What are the key implications here as you look towards the first quarter '27 readout?

Yes. So the update we provided calls for an interim analysis of the results of the interim becoming known to us in the first quarter of next year. And again, if the DSMB recommends that the trial continue, we'll be -- we'll get to the requisite target event rate by the end of next year. So the implications to the investment community and to us as a company is we just increased the probability of success. We feel very good about the trends that we're seeing. We're encouraged by the observed MACE event rate, all the individual events as well as the composite, and we believe they're tracking well for us to be able to potentially stop the study at the interim time point.

And if we're wrong or if the DSMB exercises discretion, which they fully have and recommends that we continue the trial because they're encouraged by some other signal that they're seeing in the trial and they want that data to mature, then we'll continue the trial into the end of the year. But if we continue at the end of the year, there'll be many more events that will support potentially achieving statistical significance. And as a result, the risk of success increases. So I think we've taken at this point, every step we potentially can to derisk the outcome. And as Michael Davidson, our CEO likes to say, ensure that the trial is designed and executed in a manner which allows the drug to succeed.

Ian, BJ, thank you so much for joining us, and appreciate you coming by.

Yes. And thanks for everyone sticking around until the end.

Thank you. Thanks, everyone.

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.

Good morning, everybody. Welcome to day 3 of our 37th Annual Healthcare Conference. My name is Jim Fehrenbach. I'm the COO of the Equities business here. We have had record attendance, record attendance on day 1 and record attendance on day 2. And for the 37th Annual, that actually is saying something. I would like to thank you for your support and partnership with this event. Without further ado, it's my pleasure to introduce you to Michael Davidson, the CEO of NewAmsterdam Pharma; and Yas Rahimi, who is a Senior Analyst and Managing Director. And because there's no other analyst, I'm here, our favorite at Piper Sandler. So thank you so much.

Thank you so much, Jim. Michael, so wonderful to have you. And what an incredible 2025 in terms of the execution of the study. And 2026 is another very big year for the company. So lots to discuss. I think maybe the first place is 2026, the year for PREVAIL CVOT to read out in the back half of 2026. Maybe help us understand how much visibility do you guys get in terms of event rate and how is the study progressing? And what confidence do we have that it's going to be on track for the back half of the year?

Right. Well, good morning, and thanks, Yas, for inviting us. We're excited to be here. It has been a very exciting year for NewAmsterdam, 2025, a year of execution, a year of data release and getting our BROADWAY published in The New England Journal of Medicine England Journal of Medicine and BROOKLYN and JAMA and then, of course, the Journal of American College of Cardiology, the JACC paper is going into more detail about the events in BROADWAY and how they separated and statistical power, less than 0.003 for a MACE benefit of 21%. So that's the key thing about the events that we have to track is we had a very -- we have very good data on other studies that have similar populations.

So you can estimate events and FOURIER being the most probably relevant. It was a CHD population and treated for 2.5 years. You had the 2 semaglutide trials, SOUL and SELECT, also CHD patients, not exactly the same patient populations. So you can get a good estimate of patient event rates in these high-risk cardiovascular disease populations. And so we had projected those event rates into our study going in and then you predict a certain relative risk reduction, we said it 20%. And so that is what we track.

So we see a blended rate of events. We know that the 2.5-year mark is the minimum follow-up. And so what we're really telling everyone is that the 2 reasons to stop would be hit the 2.5-year mark and we've hit the required event rates. And so we're keeping an eye on that. I would say if it does not read out by the end of '26 is all because the event rates are lower than expected, which is going to be, we believe, a very good sign because we do have excellent kind of benchmarks to know what the event rate should be. But that -- we're going to come back to the -- all our stakeholders, KOLs and update around mid of '26.

We've had a 2.5 year -- 2-year follow-up for every patient so we can get a really good handle on what all the adjudicated event rates are. I think that's the right time to come back and kind of get more clarity. Once you have that, you can get a pretty much a straight line about when you're going to hit your events.

Okay. So expectation would be mid to give an update. And based on that, either with -- the scenarios would be yes, it's on track and you could fine-tune potentially the timing. I guess help us understand if it does have to be -- the events are tracking low -- lower, that's also not a bad thing, right? So maybe help us explain...

Right. Yes, that means that the assumptions that went into the event rates were off, which is a possibility. But the thing is we have many studies to predict that. We have also AI and you can almost match exactly patient populations. So we have really good tools to identify the event rates these days. And so if we are slower than expected, I think we believe that would be a good sign that what we saw in BROADWAY is translating into an even better relative risk reduction. But we -- again, there's always a little bit of -- I think it's a blinded trial. So you're going to have to kind of consider that. But right now, what we really feel good about is the quality of the trial.

The things that we measure drop in, dropouts, off drug, those that have withdrawn from the study. And when we put our benchmarks against any other trial that's been done to date, we're exceeding all those quality benchmarks. So we feel we have a really good study, very motivated investigators. The investigators when they saw the BROADWAY trial said, "Wow, this drug is amazing. We got to keep all the patients." Those are the things that help these long trials to keep patients on drug. So from that perspective, we think we're really working hard to maintain patients staying on the drug and completing the trial.

That's wonderful. And I've already made the commitment whenever obicetrapib becomes commercially available, I will be on it, even though I probably don't have any elevated risk. But just in prevention for all of the above as I will be aging because it's an incredible product. One of the questions we still get now is, I think you guys have done a great job kind of helping us understand the differentiation between MACE-4 versus MACE-3. Is that something to still -- is there some thoughts as we go into that mid disclosure to also give an update if there's a reason to move away from MACE-4 to MACE-3? Does it even matter?

It doesn't. We've committed to MACE-4, which happens to be the established what's called the CTTC 4-point MACE. When everyone publishes they're on the line, what they predominantly publish is the cholesterol trial treatment center line, which is called the CTTC line. That's made of the 4-point MACE, which is the CHD death, coronary artery disease death, nonfatal MI, ischemic stroke and coronary revasc. That's the 4-point MACE. However, everyone does acknowledge that 3-point MACE is the harder MACE, we call it. And you want to see that also being positive as well. And so we're powering the study for both 4-point and a 3-point MACE benefit.

Okay. Perfect. Maybe next we could transition is regulatory filing. August 18, you guys announced that the EMA accepted obicetrapib LDL-C-based monotherapy plus the fixed-dose combo with ezetimibe. So I guess maybe give us an overview where are you in the process right now in Europe? And maybe also what is your partner, Menarini doing in terms of getting commercially ready?

Right. So we have, as you said, filed. We're getting -- already getting a significant amount of regulatory interactions. The typical process is going through -- it's going well. Menarini is the filer based on our agreement with Menarini. They -- what thing about Menarini is that their footprint across Europe is #1. I mean they have 6,000 reps, which is a huge sales force. They have the standard medical science liaisons and the medical affairs. And so they're gearing up for launch. This is a really big product for them.

They tend to be more generic type drugs, but they have branded drugs as well. So they have a lot of interactions with physicians on a regular basis, which I think is perfect for us. And of course, we're excited because we have very good economics on royalties and milestones. And so for us, we see helping them with our commercial team, integrating with their team quite a bit on how we're going to successfully launch obicetrapib. So again, they'll launch before PREVAIL, of course. And then for us, they get a period of time where they can establish a price.

Okay. And how do you think -- I think a lot of investors have been a little worried about the price discrepancies between the U.S. and Europe with MFN. Obviously, cardiovascular drugs are not priced at orphan pricing. So have they given any color how they're thinking about pricing and as you guys are thinking about pricing here in the U.S.?

They're doing a lot of work on different scenario planning on pricing. And so we're working with them. We cannot influence the pricing other than we can have discussions and it will be their decision ultimately what the price. But we know that we have a drug that provides greater value of LDL lowering, Lp(a) lowering, diabetes prevention, now Alzheimer's benefit. So we feel that all that will take into consideration when they do the pricing.

And so we're working with them. And we feel that whatever pricing it is, we can work with that in the U.S. as well because it is a separate company. I think that's -- we don't exactly know how that plays out. But we do think that makes a difference. And then, of course, with list price versus what actual prices end up being is often can be done in a discrete way where you're not really locked into a price that they're using in Europe on the discounting side of things.

Okay. And in the U.S., maybe you guys also are very actively planning to file the NDA in the first half of 2026. Can you give us an idea of where you are and how much of that process has been completed? What is left to do?

So we are moving forward with some of the preliminary filing requirements that the FDA needs. And we will meet with them, again, in the first half of this year to get an understanding about when we want to file the LDL NDA and then when -- for the PREVAIL data to be inserted into the file. So we've discussed that with the FDA.

Like I said, one of the things that we feel is very important, although when we surveyed physicians, 90%, the outcome study is not critical for the decision to prescribe obicetrapib, about 10% it is. And so we want to make sure that when we launch, we have maximized the label. And so we believe that having a launch that has the outcome study either in the label or soon after that with an updated label is going to be important.

We also have the RUBENS study, which is going to finish at the end of this year -- sorry, the end of '26 that we'd like to get in the label as well, which is the diabetes trial. It will give us a broader patient population to talk about with clinicians. And then the Alzheimer's data, we also would like to have that soon around launch, too, because what we're hearing from our KOLs in particular is that, that is such an important differentiator even more so now with the EVOKE-01 and EVOKE-02 studies not working. So we want to line up everything when we launch to have the whole label and/or information about the drug in the public domain to maximize launch success because you get one chance to launch and having all that at launch, we believe, is going to do what we need to make sure that everyone knows that obicetrapib can provide greater value to patients beyond just LDL-C lowering.

And another study that you guys are also conducting is the VINCENT study, which is the combo with a PCSK9, and that's on track to read out in 2026. Maybe help us conceptualize that study and the importance from those results, right? Obviously, investors understand -- want to understand the combination ability of the [indiscernible] agents.

I think the key thing is we have a lot -- this is a small study. It was really designed to talk about the combo with a PCSK9 because that's -- those orals are coming. So we wanted to be thinking about what a combo product would look like as a prototype. And so that was really the purpose of the study.

As we got more into the BROADWAY data, we realized that the data was so compelling already that we had a 50 to 150 range for Lp(a), which had a 50% Lp(a) reduction, which is really a very important patient population because we know that when the injectables come out and they show a benefit, it's going to be relegated to the above 150 and those that have heart disease already. So for the majority of patients, by far, it's going to be -- we're going to have Lp(a) levels below 150 and they may not yet have heart disease where obicetrapib becomes the ideal therapy. And so we think VINCENT will help, again, clarify how we position ourselves with -- compared to the PCSK9 inhibitors for that patient population.

That's very helpful. And team, I think one of the questions we always get is sort of a vision on how obicetrapib is very unique, right? It has multi-phototrophic effects that cause many lipid reductions as well as an Alzheimer's benefit as well as a glycemic benefit. So how do you think it's going to be used in practice? You still practice. Maybe is it once a month, right, at a very heavy...

3 times -- 4 times a month, yes.

4 times a month, wow. I don't know how you point out. But help us understand where are we in terms of current management of dyslipidemia? And how do you think obicetrapib will be used in the real world?

Right. So thanks. I think the patient care part is still my passion, and I actually see patients 4 full days a month, which is a busy clinic. And it is a great opportunity to get insights into what patients are thinking and how they go about their journey to go on to a lipid therapy. I would say care has evolved over the last generations where taking a medication was so widely accepted and you didn't get much resistance.

Now the new generation is much more -- they want to know why they were taking it, how to avoid taking it and why do I need to take this particular drug versus another. And so that is where I believe having that insights as a clinician is why obicetrapib is going to be so successful because when you think about the patient journey, they know they have high LDL. They know they have a high risk of heart disease or they already have heart disease. They are motivated to do something about it, but not that motivated. They'd rather try anything else, but taking medication for many patients.

But when you have high Lp(a) or you have diabetes or you have Alzheimer's risk with APOE e4, those patients are very motivated, very motivated. And when you have a drug that can address those 3 things, you get not just willingness to take it, but they want to take it. And so that makes a big difference. And that's why I'm very, very convinced that obicetrapib, when we do launch the drug will be extremely well received because of the patient advocacy on their own part to be on a drug like obicetrapib. And I know it's -- I guess I just have high confidence that I know -- the patients that I know, they're all going to want to take obicetrapib versus any other LDL drug, and they'd like me to also, if I can, reduce their stat dose if at all possible, while they're on the obicetrapib.

So it's all about that journey and the patients wanting to deal with these very personal things for them. The Lp(a) have a very bad family history of heart disease. In diabetes, of course, they worry about all the other comorbidities. And for APOE e4, nothing is more motivating than knowing that they don't start something soon. They're destined to get Alzheimer's dementia. So to me, it's going to be a rocket for obicetrapib for those reasons.

And where are we in terms of measuring Lp(a) in the clinic? Has it become a standardized test? Are patients understanding Lp(a) is a risk factor and managing it?

It's getting much better, I would say, even -- I've been doing it for my entire career. But if you look at the last couple of years, it's becoming more and more evident. We also have like by leading referral to the clinic now is high Lp(a). I think 1/3 of all my new patients are coming in for high Lp(a). So it's becoming more known. And of course, when HORIZON hopefully reads out positive, then the therapy is available, will have even much more widely done testing. And then I think obicetrapib could theoretically be the first oral Lp(a) therapy that's maybe not labeled that way, but it would have certainly the knowledge that it can affect Lp(a) levels beneficially.

And do you think that we have a good understanding of what level of Lp(a) reduction is needed? Like do we have a good understanding of what is the target goal?

That's a very, very difficult question. We're going to learn that from the HORIZON trial as well as others yet to come. There's many multiple trials coming. But the typical 100 nanomoles per liter decrease in Lp(a) should be about 15% relative risk reduction. That's kind of the benchmark that the epidemiology suggests.

Now whether it's a linear thing is -- would be great, but also might be a threshold thing. I think that at least what I believe is that an Lp(a) is kind of like smoking, and that is that if you have high Lp(a), your risk is elevated. If it's above 50 or 75 nanomoles. Your risk is elevated. So you want to bring it below the 50 to 75 level.

If it gets really high, that could be more risk, but it's -- usually, it's more of a factor that gets enhanced when you have other issues like diabetes or inflammation like CRP, that's when Lp(a) becomes much more of a significant factor in causing premature heart disease. Again, obicetrapib being what it is, we think it mitigates the risk not just on the LDL lowering, Lp(a) lowering, but also by the metabolic syndrome features that it improves. We think it could really have an outsized benefit on not just lowering Lp(a), but also reducing risk in those patients.

No, very helpful. One of the questions we get, obviously, HORIZON was on schedule to read out in 2025. It got pushed into 2026. I know John is not here, but he's, I think, the steering committee of the study. Do you -- I guess, we're trying to figure out, could we get HORIZON before PREVAIL? Or could it come after TBD? Do we have any...

Well I think PREVAIL is going to -- well, we heard that HORIZON is going to read out the first half of this year. So it will before PREVAIL. But yes, I think it's -- again, they're tracking events just like we're tracking events, lower than expected is probably most likely a good thing. I do think when I look back at their projected event rates from their design paper, they put in 4.6% annual event rate based on their inclusion criteria. They use urgent re assets very close to our 5% rate per year that we think is the right kind of benchmark.

So they probably had predicted a little bit too low because the LDL is only 60 milligrams per deciliter. In other words, the event rates are probably lower than that because of the LDL 60. I think they weren't expecting an LDL of 60 in the trial, which can mitigate the high Lp(a) rate. So I think it's a good sign the event rates are lower. I think they can also like I said, you can look at what the expected event rate should be. But that means readout for them is going to be the, I think, second half of -- first half of '26, yes.

Do you think that you guys did a really nice job this summer when you had your R&D Day to take the BROADWAY data and put into context of what drove that 21% MACE reduction. And I think it was alluded to like 5% of that was a contribution from Lp(a). I guess I'm trying to understand like, let's say, fast forward HORIZON comes out, whatever we get, is that an opportunity to go back to those analysis and see if the contribution is different? And what kind of analysis could you do at that time to help us understand whether it is a 5%...

Right, right, right. We believe we can. That will be -- like we said, that 100 nanomoles per liter is based on observational epidemiology. Now we'll have a true intervention trial that can model it even better. And so we'll see that will help us. But I do think what we feel about BROADWAY data is, yes, we do -- we can model Lp(a). We can also model all particles. We can also model HDL, if you want. I mean so you can look at other things that obicetrapib does, but the bottom line is you got the 21%. And so we feel that's the key thing is we already have the evidence of benefit in a relatively large trial over 1 year. And so we think Lp(a) is a very important factor, but it's not the only factor with obicetrapib that could explain the benefit in that -- in the BROADWAY trial.

And then maybe one last question. One of the things that I think always gets underappreciated about obicetrapib is its safety product profile and its ability to be combined, right? Because these patients are on multiple various agents. It would be great if you could just put it into context as a practicing cardiologist, the importance of a very clean, safe drug and then also a product profile with no CDIs and combination ability.

I cannot emphasize more. But again, being on the clinical side, the patient scrutiny on safety is just -- it's just unbelievable. They go to AI now or Google and get all kinds of information about the drug. They'll question why you pick this drug over another drug for the safety purposes and so forth, all the time, almost is universal. And so having a drug with obicetrapib with a great profile, is going to make a big difference.

Again, you mentioned the combo thing, and that's something we're exploring, of course, with -- obviously with ezetimibe already. But thinking about combinations with obicetrapib, it's a very good drug to combine. And we feel that, that's going to be one of the elements about obicetrapib that we feel that will be enhanced as time goes on. We're looking at all kinds of life cycle management options that we have for obicetrapib in the future.

Wonderful. Well, Michael, it's a pleasure having you, and it's been really an incredible journey covering your company and working with you guys. Every time I talk to all of you, I learn a lot more. And obviously, you're an incredible physician as you would -- on top of everything you do, you practice in Chicago 4 times a month, tells you how passionate you are about the field. So let's give a big applause to Michael.

Global Health Conference at Citi. My name is Geoff Meacham. I am the Head of Healthcare, Global Head of Biotech Pharma Research. Fun, fun.

We're thrilled today to have NewAmsterdam Pharma. We have Michael Davidson, CEO; we have Ian Somaiya, CFO. Guys, thanks a lot for the time.

Thanks, Geoff.

So maybe we'll just do like a quick background, Michael, you want to give like a couple of minute like pitch just sort of elevator, then we get into some PREVAIL questions, marketing.

Sure. I mean this has been a great year, 2025. We announced at the end of last year in 2024, our BROADWAY Phase III -- completed our 3 Phase III trials, which will be for the submission for regulatory approval across the world. And we had publications this year in New England Journal of Medicine and other very important journals, JACC, in particular, that showed our great data on both LDL lowering and tolerability.

And I think what everyone got most excited about was our benefit on major adverse cardiac event reduction, MACE reduction of 21% in the BROADWAY trial, which was a large trial, 2,500 patients, well over 100 events, and we saw this early signal of benefit with that 21% relative risk reduction. So we had a lot of analyses based on that, trying to understand what was the reason for this early benefit, and we have a drug that we've been differentiating it from any other lipid drug for multiple reasons.

It lowers Lp(a), which is a very prominent target. It's in development for many therapies trials to read out in the next couple of years, a very, very atherogenic particle that explains premature heart disease and people have progressive disease despite being on statins, because statins have no effect on Lp(a) and our drug lowers Lp(a) by about 50% in that 50 to 150 range for Lp(a). That's a great benefit.

Also, statins increase the risk of diabetes modestly, about 20%, especially in high-intensity statins and obicetrapib lowers the risk of diabetes. We showed that in our BROADWAY data. Statins also differentiate lower large particles and they leave the small particles behind and the small particles are much more atherogenic and sticking the arteries more readily.

And then we're able to prove, most exciting, I think, for a lot of the KOLs in the field because it's a novel finding is the Alzheimer's prevention benefit. This has been a part of the story of -- from the beginning of NewAmsterdam when I started the company with John Kastelein, we have seen the data from the Mendelian randomization studies showing that when you have ApoE4, which is the most prominent Alzheimer's gene, about 2/3 of Alzheimer's patients have ApoE4 heterozygote. And then unfortunately, you have a homozygote, you have tenfold increased risk of Alzheimer's.

We saw a very prominent benefit on this really good biomarker, p-tau217, which is increasingly becoming recognized as a valid marker that changes with improved treatment and very highly predictive. And if you lower it, it predicts benefit. We saw a great benefit in our BROADWAY trial, especially in the ApoE4 heterozygote and even more so in the homozygous patients. So at the end of the day, we feel we have a very, very differentiated drug. It's the LDL plus story efficacy that lowers LDL in the 40% range with 50% with the combination with ezetimibe.

But the other benefits that really differentiate the drug as a very well-tolerated oral, easy to take therapy. So we feel we're in a good place. We've seen, of course, the value being recognized by the community, the medical community. And we also had some great changes in data from other external sources, the VESALIUS trial showing benefit of LDL lowering in a broader population, more of the lower-risk secondary population, a primary prevention population. So those are going to modify the guidelines.

So now we're back to this time where were maybe a decade -- more than a decade ago where it's lower the LDL, the better. And now we have even more patients that need or deserve more effective LDL lowering. So we're think we're in a really good spot with our drug and what we've shown and where the unmet need is growing based on new science. So for us, this is an exciting time, and we look forward to next year.

PREVAIL being our key outcome study. It's going very well. We're following the quality metrics very carefully. And we're really, really proud of our adherence to the study protocol. The drop-in, dropout rates are low within better than any other trial we've seen as benchmarks. And so that study will continue to progress in '26. We have the 2.5-year minimum follow-up will happen around October, which is the first time period where the study could be continued as long as we have enough events, which is the key also 2 factors, time, 2.5 years and then events have to track to complete the trial.

Yes. Let's -- I guess, Michael, let's talk about PREVAIL and the clinical piece, and we can get into kind of the market component. So you mentioned you're comfortable with the conduct of the study. Just want to get maybe an assessment or a view of -- I'm assuming that you retest your assumptions as you see events between the different arms. Maybe talk about like what you can do to just ongoing basis to monitor PREVAIL and maybe what gives you maybe the conviction in the -- at least in the timing of it. I know, obviously, you're pretty convicted in the ultimate outcome, right?

Right. So we -- again, because again, BROADWAY was a mini PREVAIL, it was meant to be a way to derisk PREVAIL for the skeptics because of the CETP kind of molecule issues. So we wanted to make sure that was -- that BROADWAY itself was going to have a lot of events that we could look forward and how we also guide the event prediction for PREVAIL.

So we based PREVAIL on the FOURIER trial, which is one of the prominent Repatha trials. That's a CHD population. And those patients had an event rate that we -- basically how we determine our sample size calculation with a 20% relative risk reduction. So in whether it's just because that we did a good job predicting, but BROADWAY was exactly what PREVAIL was at 1 year. It was exactly the same event rate. So we feel that was a good benchmark of event.

Now the thing is the BROADWAY data was greater than expected about the risk reduction at that time point. So we're tracking that. I mean if our event rates are falling short of the predicted progression rate, you can anticipate either we're wrong about our projections, which we don't think we are but -- or the drug or is performing better than expected. So we'll have to keep a track on that. We'll get back to the community more about the timing of that as we get more events adjudicated.

We're doing that on an ongoing basis. But I think the quality metrics are great, and now we'll track the events, and we'll see where we are. I think we're expecting to come back to the community, the investor community in about the middle part of next year with an update on the timing of PREVAIL.

Yes. And then just related to that is the regulatory time lines in the U.S. because remember, our goal is to really take advantage of the rare opportunity of having outcomes data available at launch. So once we have a better handle on timing of PREVAIL readout, we can also give you an update on when we plan to file for U.S. approval.

Yes. That makes sense. I know you guys have been talking about diabetes and Alzheimer's benefits associated with obicetrapib. I'm assuming that PREVAIL has enough power and data points to even directionally assess that as well?

Well, diabetes for sure. There's enough -- Alzheimer's is the check -- the part we have -- we cannot do is we cannot get cognitive testing in the trial. So we will have biomarkers again.

Like p-tau, biomarkers.

p-tau and neurofilament light and GFAP, all the amyloid 42/40s, all the different biomarkers, which are showing up as a really good prediction of future cognitive decline. So we have those as well in PREVAIL. So we'll have ApoE4 for phenotyping again. But now we'll have a much bigger sample size and we'll have a longer duration of follow-up.

But we have promised to get back to the again, to the investor community, the medical community, we are planning another study for Alzheimer's, a prespecified trial that focuses on the patients in BROADWAY who responded the best, which are those that have ApoE3/4 or 4/4 at a certain age. And what's really good about the data, we published it in a very prominent journal, Journal of Prevention of Alzheimer's just a few weeks ago. This actually just online, just got published this week that the data shows, which is what you'd hope to see is that the drug worked best in those where p-tau was increasing. And it turns out p-tau is increasing in those that are older, especially those who are older with APOE3/4 or 4/4.

So exactly what you would expect of a good biomarker for predicting Alzheimer's disease. That's where the drug showed the greatest effect on reducing those -- that biomarker significantly as well as neurofilament light and GFAP and amyloid 42/40 ratios were all consistently improved in the patients that got obicetrapib. That was published this week. And also, I think what we also believe is helpful to us Unfortunately, the GLP-1s did not work, EVOKE-1, EVOKE, EVOKE+ did not work, and we'll see tonight the presentation, but we've heard that there's no effect on p-tau217 in that trial. And so again, it gives us, again, a negative showing that you don't improve cognition, you don't see improvement in p-tau.

On the other hand, just published this week as well in JAMA was the TRAILBLAZER trial showing that the improvement in cognition is highly correlated with p-tau217 changes. And so these are all starting to line up to give us a lot more we've always had the confidence, but a lot more of addressing the skeptics that all you showed was biomarkers getting better. Is it really going to matter at the end of the day when it comes to preventing Alzheimer's disease.

And we believe that the data is continuing to strengthen our argument that our BROADWAY data is very compelling. We know that a lot of the KOLs believe that already. But we'll get -- as we get the other study underway and continue to highlight this benefit, we believe this will be one of the -- another really great differentiators of obicetrapib compared to any other LDL lowering drug, and we'd like to ultimately see it approved for Alzheimer's prevention. That's our goal.

So is the idea that you see rising p-tau levels, tau correlating, I think, with more cognitive declines, meaning like moderate to severe. Is that a fair characterization of the baseline that you were the patients that you [ saw ] in BROADWAY and BROOKLYN?

Right. Well, for example...

Clinically diagnosed?

Unfortunately, we don't have cognition. It's just a very -- cognitive testing is something that requires a lot of expertise. We just didn't have that in the trial. So we will be doing that in our upcoming trial. We'll do cognitive testing. But what we, again, believe is that nothing predicts better the conversion of normal to MCI or MCI to stage -- later stages of Alzheimer's than p-tau217. And so that -- there's been 10 publications in the last few weeks to continue to strengthen that argument.

So we believe that over time, this will become something that will really highlight the differentiation of obicetrapib from any other drug out there. It's very -- again, other benefits is safe, well tolerated, easy to take. So those are things that are going to make it even better uptake among those that you might have concerns about taking an anti-amyloid antibody, which can have serious risk factors, so safety issues with it.

I guess let me ask you when you think about the -- from PREVAIL, if you had the same trend, and let's say, but you saw obviously a stat sig MACE outcome. So that's a home run. You can file with that. Would you want to -- what would be the range of outcomes? Like would you have descriptive data on p-tau in the label? Would you ask payers to -- like would you want more value for it if it had a trend on Alzheimer's, obviously, no cognitive data. Just one the range...

We are going to look exactly to that point. We do believe with this type of trial, we can look at certain functional outcomes, conversion to people going on drugs for dementia, those kind of things in our whole overall -- as you do these outcome assessments, you look at a whole variety of things that go along the traditional MACE benefit. You can look at -- same thing for the diabetes benefit.

We'll see -- we already saw that in BROADWAY, decline of people going on the new drugs for diabetes, for example. So we can see similar things in PREVAIL. But the key will be our own prospective trial, which we are starting sometime next year. And that will be the basis for a population that we think is well suited for obicetrapib, which are those that have a certain age and they have ApoE4 either homozygote or heterozygous.

Is this a Phase IIb?

Phase IIb, yes, we're calling it Phase IIb, but we believe there's a chance, very low chance, but there's a chance it could be a basis for accelerated approval.

Is there a scenario where you could maybe get another entity to fund a large-scale Phase III that way, you don't have to take the financial risk, but you obviously, if it works.

There are like the gates -- we're looking at all kinds of things.

Yes, be creative with...

Obviously, Bill Gates had a father who died of -- that's an example. We -- these are things that we can look into. We feel that there are. But at the end of the day, though, because the population we chose such a high risk to convert to Alzheimer's. It's not what people think when it comes to cost. And so we feel that after PREVAIL, when we're a company that has a cardiovascular drug with well-proven benefits, we can proceed with a true outcome study on our own, if necessary. Yes.

Has the -- we had Marty here yesterday from FDA and just talking about creative ways to accelerate development to remove kind of the white zones where there's just sort of dead time with the regulator. Are there -- if this works in PREVAIL and you see the Alzheimer's benefit, are there ways to convert your Phase IIb to a pivotal and...

That's how we're looking at it. I mean it would be the Phase IIb, that's how we're phrasing it. But we also had all the supportive data from PREVAIL.

You'll have baseline sort of cognition and all that.

Right. Right. You're right.

Okay. Yes, that makes sense. Awesome. What's the -- has there been science on the mechanism of CETP? And is it classic like sort of anti-inflammatory?

Well, it's anti-inflammatory in that it removes the inflammatory stimulus, which is the oxidized hydroxycholesterol. So in other words, we know that inflammation is a big factor in Alzheimer's disease. as is in atherosclerosis. The analogy I like to give is you got a splinter in your finger and it's inflamed, what's the best way to get rid of the inflammation is take out the splinter. I mean the same thing is true for the brain. If you have inflammation due to hydroxycholesterol, the best thing to do is remove the hydroxycholesterol, it's what HCL does. So we feel that is the core pathology behind ApoE4 that we address with CETP inhibition.

When -- maybe a question for you, Ian, when you look at sort of consensus expectations for obi, to what degree do you think they bake in kind of Alzheimer's and diabetes benefit -- is it just MACE and cardiovascular sort of success blocking and tackling? Or there is another dimension to what you think the Street expectation is?

Geoff, that's a loaded question. I could turn that right back to you and ask you what you're assuming in your model. But if you look at consensus, it's hovering around $2 billion, $3 billion in peak sales. During our R&D meeting in the summer of this year, we obviously shared with you what we think the peak sales potential is, and it is $8 billion plus. So there is a disconnect. And depending on the model you look at, there are obviously many sources of variability. None of those models assume any value for Alzheimer's.

And I think as we've said to you before, the value in MACE is having a positive study, it's really less to do with the number. As long as we have a successful study, we have a validated mechanism and we inherit the class label. And this is an important point, the FDA has harmonized labels for lipid-lowering therapies. So we benefit from that.

I just don't want to be in a situation where you have a positive MACE outcome and then the Alzheimer's stuff is trending, but -- and then that's a disappointment, right?

No. Look, I don't think it's -- it could be, it's possible. But look at our data from BROADWAY, it's...

Unequivocal.

They're unequivocal. The p-values are 0.0002 or something like that. Yes. So it's unequivocal.

You can get to $7 billion or $8 billion without any diabetes or Alzheimer's benefit.

So our -- yes, our $8 billion plus is entirely predicated on CV.

Yes. Okay. Okay. And I know you've talked -- you spent a lot of time probably talking to U.S. payers, what about the global -- is there -- what sort of leaps do they have in terms of how they -- I guess there's no -- there's a clinical history with CETPs that you guys are sort of undoing. That's mostly a U.S. phenom. Is there anything outside the U.S. that you have to overcome with regard to CETP attitudes or...

Yes. I can take that, I guess. I think we've deployed MSLs in the field for 2 years now because that is an issue we had to address. And I think they're making a lot of headway. Of course, the data itself is the best way to get the skeptics on board. And our JACC, The Journal of the American College of Cardiology paper, I think, which was a subset of broadly that showed the MACE benefit more clearly was a very well-received publication showing the statistical difference after 6 months was like 0.003, very statistically significant difference in MACE in that study. So that's a big factor.

In Europe, we also have a lot of KOL support, many publications. One of the things that NewAmsterdam excels at because that's our background. I mean, both John Kastelein and I are in academics. I'm still seeing patients at the University of Chicago. So we're very embedded in the academic community, and that's where we are -- that for us is our home.

So if you look at the -- what we've done on the publication side, New England Journal of Medicine, Nature, JACC, JAMA, all these things have really, I think, impacted the medical community and where we're going with obicetrapib. And so Europe, we have our Menarini partner also engaged with very much outreach with their MSL network already meeting with KOLs. And so they're preparing for the launch. And what's great about Menarini is it may not be that well known in the U.S., but in Europe, it's very well known. It has the largest footprint of any company when it comes to cardiovascular medication. And so we feel we're well -- we have a great partner there to help us in the launch.

Awesome.

I mean just to share some numbers with you, Menarini has 6,000 sales reps in Western and Eastern Europe. that's a sales organization that we could never imagine being able to build on our own. And given the economics that we have retained on the drug with royalties going up to mid-20% and milestones that are still owed to us, which are north of EUR 800 million and a deal that was struck when we had Phase II data.

So to have that quality of a deal with a partner with this level of capabilities, and Michael mentioned, they're amongst the leaders. They're #1 in primary care. They're #1 in cardiovascular care, and they're top 3 in the endocrinology community.

That's helpful. Let's talk about -- so we had a session with Merck earlier when they were talking about their oral PCSK9. And there's a bit of a mixed view of that just given the food effect, but I think the data are good. But there's a discussion of statins are not enough. I would probably -- most people agree with that, right? So what are maybe some of the range of guideline things, assuming that you do have some success in PREVAIL, how would you imagine guidelines playing out with respect to PCSK9 as one vertical, CETP as another, maybe Lp(a) is another looking out a couple of years?

So I think VESALIUS was a big help because of the -- it opened up another large segment of the population proving that getting LDL levels below 55 reduces mortality. I mean that was the key thing. And so that mortality benefit, which was not seen in FOURIER because it was shorter, it went longer with VESALIUS, they went to almost 5 years, which is quite long, and they saw the mortality benefit there significantly.

So that means the guidelines are very much affected by that type of data. So what we're going to see basically anybody with atherosclerotic disease, and it could be as early as a calcium score, you had a calcium score, you went to your doctor, you're 50 years old, you have a plaque in your arteries. You now need to have your LDL below 55. What does that mean? -- for the population is a huge change in the number of people that need to be more aggressively treated and statins alone are not going to be enough.

So that brings us to what you need to add to statins. And we'll have an LDL lowering of around 40% and then a fixed-dose combination around 50%. Merck, oral PCSK9 will be in that 55% range. The injectable similar. So they'll have LDL lowering, but we're still in the same range. And the advantage that we would have, of course, is the -- we don't have the food effect or the taking it without 8 hours of fasting. It's like Rybelsus. And you can't take any other drugs with it. So that becomes problematic. But it I see it more being utilized for those that don't want to take injections on Repatha. The more of that type of patient.

But if you want a CETP inhibitor and all it brings, you don't really compromise the LDL lowering efficacy because you have a 50% combo pill lowering LDL. But what really drives the benefit based on all our research is the other benefits, the Lp(a), the small particles of diabetes reduction and now the Alzheimer's benefit, we become the dominant go-to drug after statins. And for a majority of patients who are on a statin, if they get obicetrapib or obicetrapib with ezetimibe, 90% plus are at goal below 55%.

So -- and I think that's the message we want to get out there. These are all great drugs. They all have a role to play. But for the -- when you have that individual patient in front of you, you think about where I need to go to get them the goal and what else I can provide benefit-wise to them, we believe obicetrapib will become the go-to option for those patients, especially because of the tolerability and safety, which for most patients is the #1 issue, right? They want ease of use. They don't want any side effects. And for them, that's the most important thing. And when you can tell them, you can lower their Lp(a) and you can lower the risk of Alzheimer's, you got a much more motivated patient as well.

And maybe, Michael, talk through the Lp(a) trial you guys are running with PCSK9. So how should we view that in the context of kind of the body of work on obicetrapib?

Well, we already have a lot of data on Lp(a) from our BROADWAY and BROOKLYN and our TANDEM study, all showing this 50%, we published the pool data, 50% Lp(a) lowering in that 50 to 150 range. And so that is a benefit you cannot do with any other oral agent. And we won't have an oral agent that can lower Lp(a) to that degree until maybe the Lilly drug comes out in probably 5 years from now, 5, 6 years from now. So we have -- we'll be the go-to oral agent for lowering Lp(a).

And then hopefully, we're going to have the injectable Lp(a) drugs that are serving the over 150 Lp(a) patients that have already existing heart disease. And that will be specialty priced probably that's how they were set up. But for the other patients who have high Lp(a), which is the 90% of the other high Lp(a) patients that have Lp(a) below 150 or they already do not yet have heart disease, we see obicetrapib as being the go-to therapy for those patients predominantly.

So we see this as a really important differentiator from any other drug, including the PCSK9 inhibitors do lower Lp(a) by about 15% to 20%, 25% maybe in some studies, but we're double that with our data. So we feel that if you're looking at an Lp(a) patient before you, which is now my leading referral in my clinic is high Lp(a). These patients really want something done because unfortunately, a lot of them have very bad family history. So they know the basically the risk and the complications of high Lp(a) for their own personal reasons. that they're going to really be motivated to take obicetrapib for that reason as their option.

What's the one thing is that you guys don't have to worry about baseline Lp(a). You don't have to worry about -- there's a lot of things that you don't narrow the opportunity for your drug. Some of the Lp(a) drugs have to worry -- have to focus on just tiering, right?

Right, especially for the payers. I mean the payers are going to say, do you have established cardiovascular disease and your Lp(a) above 150? Because -- again, they will be specialty priced. So they'll go through prior authorizations. If you don't hit those criteria, the payers aren't going to pay for it. And so...

What's your view of the -- I guess there are 2 sort of cynical cases we had a we had at Cleveland Clinic, I think with Steven Nissen, who was unbelievably bullish about the Lp(a), but he's like, I don't know the actual percentage in the real world of who this is because people that come in to see me have known cardiovascular disease.

So if you take 1,000 people, I don't know how many you're going to read negative and diagnostics is an issue. And the other thing is like you can live for 30 years with higher risk and maybe not have an outcome. And so you have to just focus on the people that have comorbidities and high Lp(a). Those are some of the nuances. Again, none of them affect you from a...

Right, exactly. Yes. I mean that's true for anything. But yes, you're right, the patients with high Lp(a) that do the worst, those that also have high -- like inflammation, high CRP, they have diabetes. Those are things that you also know increase the risk of other genetic factors involved that I'm interested in that may make the Lp(a) risk double or triple what it otherwise would be.

So those are all things you can -- we can do precision medicine better to select the patients that are most likely to benefit from Lp(a) lowering. But that's the beauty of obicetrapib is you'll be using it anyway for LDL lowering. So why not get the benefit of that Lp(a) lowering with your therapy, which is kind of like a bonus. It's a bonus benefit.

And you can make that statement are quite broad because there are many reasons to use obicetrapib. They're really none to choose something else.

Yes. That's exactly right. Well, just in that maybe commercial context, Ian. so when you think about the companies that have gone through the White House this year and gone through kind of the MFN scrutiny, I know you guys are not ready to have those conversations, but when you are, how do you think about a drug like obicetrapib, which has global appeal, but to try to harmonize like the OUS and the U.S. kind of net price.

Yes. So you had a -- you had a very interesting lunch session where we really got to hear about the goals for the administration. And I really liked the overarching goal is to harmonize pricing globally. That doesn't mean just simply bring U.S. pricing down. It's really to bring international pricing higher.

And as you think about the steps that companies have taken, so obviously, there were 18 companies that were given letters from the administration, right, and we were asked to come to the negotiating table. We'll benefit from learning from all of them. We're not going to be the ones -- we're not going to be the trendsetters here. We're not going to be the company that establishes a new algorithm for pricing on a global basis.

What we can say is the drug delivers a lot of value that goes above and beyond LDL. Our overarching goal is to make sure we have broad access at the time of launch. I think we've all learned from the critical mistake when the PCSK9s were first introduced to the market from a pricing and discounting standpoint. So that's been corrected. We just want to simply participate in that pricing paradigm.

Yes. To what degree is this is mostly you guys taking a leadership position? Or does Menarini help inform the OUS like initial pricing? I know they're obviously there for commercial distribution, et cetera.

So contractually, they will set the price in Europe. So we have a great working relationship with them. So we're working together on the global branding, the initial strategy, the commercial strategy. And obviously, there's a lot of data that supports pricing decisions, which they're very well versed in.

The reality is there is differential pricing in Europe for the lipid-lowering class, and we should expect that for our drug as well. I think there are steps legislatively that have been taken where -- and I'm specifically referring to Germany now where the net price is not disclosed. So I think it's the same situation as we find ourselves in the U.S., where we're all aware of what the gross price is, but what's been negotiated is often unknown.

The good thing for you guys is though, like you said, I mean, you're not -- and you said it well, you're not -- you're getting all the other benefits for I'd say, minimal depending on where you price it, but less -- you're getting a MACE benefit in theory, locked in.

No, you're exactly right. I mean if you think about health economic studies, and we're obviously working on those now, the benefit we provide goes above and beyond other therapies. And there's a real dollar value, real dollar savings that we're providing with our drug.

I'm assuming with PREVAIL, you have all those -- the economic outcomes also associated.

Yes, we're going to definitely -- that's a big part of what we're going to do. We're doing with BROADWAY 2. We're going to look at economic outcomes. Yes. I'm always been a big fan of that. Other studies that I've done, I look at economic benefits that you achieved by lowering LDL cholesterol. Yes, you make that -- that's also a big part of your payer argument, too.

Yes. So Alzheimer's Phase II, you have the Lp(a) trial? Are there any other?

Yes. We have the RUBENS study. We hope to get done by the end of next year, which is a diabetes study.

And the other ones are the HORIZON trial for Lp(a) that should read out in the first half of next year. And the one thing that Michael mentioned earlier, the impact of VESALIUS in terms of the updates to the treatment guidelines. And I think that's one of the most understated milestones and drivers next year because it could literally increase the market by either 50%, 60% or 100%.

Do you find that when you talk to KOLs that maybe some that are more academic and run trials versus those that are more guideline driven. I think BROADWAY -- I think PREVAIL is going to obviously dictate the sentiment, right? But do you have a sort of a situation where the BROADWAY and BROOKLYN data are enough to say, look, CETP, like we're good with the prior baggage or...

No, I think -- no, we know that for 90% of doctors, they're believers, but we have the 10% that need PREVAIL. So that's why we're not launching without PREVAIL data, because it is a minority, but it could be a vocal minority. We don't want any issue to be involved when we launch the drug. So that's...

But none of the KOLs are thinking like Alzheimer's or any sort of neuro or metabolic benefit on diabetes?

For us, you mean? No, they are as far as like -- I would tell you though, again, I know they're lipidologists or cardiologists, but they're actually extremely excited about the Alzheimer's benefit. And so the neurologists a little bit more on the skeptical side because they've been such a big advocate for the amyloid hypothesis, and it's kind of like been driving the thinking for more than a decade.

But if you go back, it's interesting, you look at the literature, if you went back another decade before that, almost all the literature was of the lipid metabolism in the brain and how that affected Alzheimer's. And then they went over to amyloid, not realizing, I think, that the amyloid production was stimulated by the abnormal cholesterol in the first place. So that -- so taking the amyloid out, you might have some benefit. But the best thing you can do is improve the lipid metabolism, which what obicetrapib does.

But nevertheless, we have the -- we believe that the lipidology, cardiology community are really embracing the Alzheimer's benefit in a big way. We're seeing the brain heart health continuum really coming together. The stroke -- as you know, stroke is already an LDL-driven dementia risk. So LDL lowering is one of the key things for dementia prevention already for stroke reduction.

Have you looked at are there other benefits like renal clearance?

There is, yes. We already have -- we published on that, too. Renal improvement is also evident. We'll have more data on that we're looking at. Of course, Prevail will be a much bigger sample size for that. so that's other things about obicetrapib that are really differentiating it across the board as far as -- it's not surprising because one of the most prominent longevity genes is the CETP loss of function. And so if you look at all the different longevity genes that are out there, that's one of the top. So it's not surprising that it affects a number of other -- all the organ systems that are involved with aging.

Okay. Michael, Ian, thank you very much.

Thank you.

No. Thank you.

Thank you.