Do you hear me okay? I'm Michael Davidson, the CEO of NewAmsterdam Pharma, and I'd like to welcome all of you to come hear about our new science and information about obicetrapib. When we rang the bell in January of 2023, you know, we promised as a company, a small company, that we would work as fast and as diligently as we could to bring obicetrapib to patients. And I wanna really be very complimentary of the team. We really delivered strongly on our commitment to enroll the trials as rapidly as possible, develop the company to be ready to launch this drug if necessary. And we've doubled the size of our company to achieve this, with offices now in Amsterdam, Miami, and in the Philadelphia area. So we completed enrollment in BROOKLYN phase III trial. Results will come in the third quarter. We presented our ROSE2 full data at the National Lipid Association. Our top line Japan data, phase II results, were also presented and published, and we completed BROADWAY of our large, much larger phase III lipid trial. We released our initial Alzheimer's data, which I'll share more details with you later. We had our very effective development of our fixed-dose combination and moving forward with the TANDEM trial, which is underway and enrolling actually ahead of schedule. Just announced at the end of April, the completion of our enrollment of our large CVOT trial PREVAIL, again, over-enrolling that trial in record time. So this is... Very proud of the team that has accomplished so much as a small company to deliver on our promise to bring obicetrapib to patients as quickly as possible. Here's our team. I just want to introduce a few people in the audience. I'm really blessed with a tremendous group of people that are passionate, like I am, for preventing heart disease. Just want to, of course, start with our Chief Science Officer, Founder, Co-Founder with me, John Kastelein. Doug Kling, who's been with me for all my previous companies. He runs the exceptionally fantastic clinical operations group, is in the audience. B.J. Jones, you'll hear more about him from him later. He's our relatively new, but tremendous accomplishments today already, as our Chief Commercial Officer. Ian Somaiya, well known to many of you, in his work, as an analyst and now, with multiple extensive experience as a CFO of public companies, is here with us today as well. And also wanna not leave out Sheng Chu, who's our Chief Manufacturing Officer, who behind the scenes, has delivered tremendously on having all the drug to the sites, as well as getting our drug ready for commercialization in the future. So we have a fantastic team, and hope many of you have a chance to meet each of them individually, maybe during the break or after the session is over. So as many of you know, I'm actually still see patients at University of Chicago. I run the lipid clinic. I see patients four days a month too. I still love seeing patients, and that's why I keep doing it. According to my commercial colleagues, I'm in the top decile of writing lipid drugs, so I'm a very, very busy practitioner. Because I do have this passion for preventing heart disease, it is part of our whole mission statement. We are advancing a new life-saving treatment for cardiovascular disease and lipid-related disorders, and we're prioritizing patients with high unmet need and those underserved by current therapies. I see this every clinic I'm in. We have many patients who cannot achieve the adequate LDL goals for multiple reasons, not enough other options to consider, intolerability issues, other factors that we don't have the right drugs for yet. We know that heart disease is still the leading killer by far, and it's getting worse. That's an important message. We have actually gone backwards by more than a decade, and heart disease continues to be a leading cause of death worldwide. Here's the agenda. I'm gonna start off by giving a clinical update. Then I'm gonna turn over the floor to John Kastelein to give us a science update. This is... We're a science-driven company. You know, John and I are both academic clinicians, and science is what drives us, and I think you're gonna be very excited about all the science that we've been able to develop around this molecule and this field that goes well beyond just the LDL effects of obicetrapib, and we wanna share that with you today. For the first time, we're gonna have B.J. get up and talk about the commercial update. He's had basically six months on the job, well, maybe a little bit more, and he's put together already a tremendous team, has great insights into the market, and he wants to share with you, you know, his vision for how we can potentially launch this drug in the coming years. We'll have a Q&A to discuss any questions that you have from the audience, then a break, and then we have a very distinguished KOL panel, Jorge Plutzky from Harvard, Ann Marie Navar from UT Southwestern Medical Center, and Ashish Sarraju from Cleveland Clinic. These are tremendous thought leaders, and we look forward to their comments. We're gonna have some specific questions to ask them, and you, you'll have a chance to ask questions as well. We'll have some closing remarks about, you know, tying this all together and where we're going in the future. So I mentioned this already, but we noticed the latest data has been not going well for heart disease, and there's many factors to consider, but, you know, one of the things that we feel is a major factor is the guidelines were removed in 2013. Goals were removed from the guidelines in 2013. There was reasons for this. There was really lack of evidence of adding to a statin to further lower events, but since then, we've had many trials to support, you know, lower is better again. I think it was, I opposed it personally at the time, and I think it was a mistake, but I think we'll show you later, we're starting to see traction back to getting goals again into our approach to patients for preventing heart disease. And you'll see the LDL levels basically flatlined. They've not really improved since those new guidelines were implemented. So the challenges for us, for as a country and worldwide, is to figure out a way to make this curves go back down again and reduce the risk of heart disease. And one issue that's been well documented is that, you know, statins are the mainstay. They reduce risk, lower LDL. I believe personally, I've been saved, my life has been saved, from statins. My father died at age 47 of a heart attack. I've been on a statin since I was 30, when they first came out, and so I think it's made a big difference. Other members of my family had heart disease very prematurely. So this, these are fantastic drugs, and they made a big difference in preventing heart disease. However, there is still what we call residual risk. You know, that is the risk that continues despite adequate statin therapy. And the new evidence I described, this is just one small part of that new evidence, continues to show that part of that residual risk is getting the LDL levels down lower, you know, maximizing LDL reduction to achieve greater relative risk reduction. We see LDLs down as low as 20, having lower event rates in patients with heart disease. But other factors are responsible for residual risk. Not just LDL, but we know about inflammation in residual thrombotic risk. And then I wanna talk a little bit about, and John will go into more detail about where obicetrapib is differentiated, you know, from any other LDL-lowering drug by its impact on these other parameters. So my previous company, Corvidia, interleukin-six antibody, was acquired by Novo, and it's well underway to phase III trials for inflammation and heart disease. We have other options that we're also exploring in that field. But when it comes to the residual ApoB, LDL, small LDL particles, obicetrapib does a fantastic job, as we'll share with you later, on reducing this part of the residual risk. I use a simple way to explain it to patients. You're on a beach, you have a bucket of sand or a bucket of pebbles. They both weigh the same. They both have the same milligrams per deciliter, weight per volume, but the bucket of sand has a lot, lot more particles, and that results in greater cardiovascular risk. And obicetrapib, we'll show you the data, it has a 90% reduction in the amount of small particles, which is the residual, the majority of the residual particles when someone's on a statin. Of course, Lp has become a very exciting target. You know, many options are in late clinical trials. We'll have a readout next year from the HORIZON trial, and that we feel very optimistic it's gonna show a benefit of Lp lowering on reducing cardiovascular events. And that benefit, we believe, with obicetrapib, can be part of the treatment algorithm. We're not gonna be seeking indication for this, but as we share with you later, we have very prominent effects on lowering Lp that could be an option to consider for patients that do not have the super high levels of Lp above the ninth percentile, where the trials are being focused, but those that have elevated Lp, where, you know, there could potentially be benefits for a reduction. And then another very prominent benefit that's been demonstrated across the class of CETP inhibitors is a reduction in risk of diabetes, the progression of prediabetes to diabetes, and then actually converting diabetes to non-diabetes, with this class of drugs. And we believe this is through the HDL-raising mechanism, which is so robust, and even more so with obicetrapib compared to other CETP inhibitors. And here's the landscape, as it is now, and we're gonna talk later, especially with our KOLs, about, you know, why are these options just not being utilized effectively, for reducing LDL levels and thereby reducing the residual LDL risk, for patients? And there are other oral options on the horizon. We're actually very excited about the Merck oral PCSK9, 'cause it does speak to the strength of another oral agent, and it has to date a really good efficacy and safety profile. But it does- it'll still have issues that are problematic regarding the food effect, very prominent. But one point we wanna make today is that obicetrapib has these differentiating features, the small LDL particles, the Lp(a) lowering, and the diabetes benefit that distinguishes from any other LDL-lowering drug. So we encourage more and more options, more and more oral options, which are necessary to get most patients to goal. But obicetrapib itself has some key differentiations, which we believe will be highly appreciated by the clinicians in the field. And the unmet need is just, something that we haven't been able to fully put our hands around with, with options available today. So 30+ million Americans need more LDL lowering despite the standard of care. And our monotherapy, based on our pooled phase II data, lowers LDL by 43%. Then, with our fixed-dose combination, we're gonna talk quite a bit more about that today, lowered LDL close to 60%, and the drug has very excellent tolerability and safety in phase II. And we're not gonna share with you any blinded safety data, but we can tell you with great confidence that we're seeing no issues on safety in now thousands of patients in all our phase III trials. That we're blinded to safety, 2-to-1 randomization in both BROOKLYN and BROADWAY, one-to-one randomization in PREVAIL, with, you know, we have about over 10,000 patient years of safety, and we're seeing an excellent safety profile with this drug to date. Again, majority of that is blinded, and we'll have the full data readouts later this year. So we, again, believe that a simple, once-daily, oral CETP inhibitor that lowers LDL, is convenient, is what's necessary to address this very growing unmet medical need. And then, another message that we've been saying is that with our experience, we wanna not just have a better drug, but a better clinical trial program to develop this drug. We've been very fortunate to learn from the past about what was done right, what could have been done better, you know, to maximize the benefits of a drug like obicetrapib. And what's the learnings that are relatively recent are that the benefits of LDL lowering are driven by absolute LDL reduction, and then the other major issue is duration. You just can't expect a benefit within a short period of time. And so we have designed our trial to maximize a higher absolute LDL at baseline, and therefore, a greater absolute reduction in LDL to support a greater MACE benefit. And then, duration,two and a half- year minimum follow-up to maximize the reduction in events. If you just take a number of trials, FOURIER being the most obvious, it was the Repatha trials, only 2.3 years duration. If patients were on the drug for just a year, the relative risk reduction went from 15% to 20%. So a big difference just by having a one-year minimum follow-up, and we have a two-year minimum follow-up, two-and-a-half-year minimum follow-up for our patients. And then the other benefits that I alluded to, we'll go into more detail later, definitely demonstrates a differentiated profile that's gonna be a very exciting additional element to what we don't have yet in our armamentarium for treating elevated LDL cholesterol in high-risk patients. And we also, learning from the past trials, we're able to identify in the CETP inhibitor class, which is REVEAL. REVEAL was the eureka moment for trials. It showed not just that CETP inhibitors worked based on LDL lowering, but also there were subsets of patients where that reduction was even greater: high triglycerides, low HDL, high ApoB, high baseline LDL, high Lp(a). Those are all risk enhancers that we added to the PREVAIL trial, again, to maximize the relative risk reduction. We also learned that heart failure patients do not benefit from LDL treatment, and in the trials that we looked at, if you took out heart failure, the relative risk reduction, again, went from 15% to over 20%. So we removed heart failure patients from the trial for that reason. So we wanted to enhance the trial for those more likely to benefit, and then removing those that we know that it's really too late to achieve a benefit with LDL-C lowering. Just to share with you our modeling for how to think about how BROADWAY results, which has very similar patient populations to our PREVAIL trial, should translate into a significant relative risk reduction. I'll share with you in a minute our baseline levels of our trials, but the LDL of PREVAIL is 103. We're very pleased by that. 43% and based on our phase II data, should translate to a 44 mg/dL drop in LDL. That should, based on the CTTC line for LDL, mean over 20% relative risk reduction. Similar analysis for non-HDL, 34%, 45 mg/dL drop.... And then for ApoB, kind of what many feel is potentially a better risk predictor, but not as much robust evidence for that as we do for LDL cholesterol. But you can see over 20% as well, looking at ApoB reduction based on our modeling from our phase II data. So it, no matter how you look at it, LDL, non-HDL, or ApoB, you know, we should achieve over a 20% relative risk reduction assuming we get comparable LDL lowering in PREVAIL that we saw in phase II. And the BROADWAY readout will help better inform this model. So let me now move on to our clinical trial data and what you're expecting to see over the next several months as we read out the data. We had the, I guess the word courage is the... or chutzpah, I guess, is another word to use, to start our outcome study at the same time as our LDL trial. So we knew starting out, we'd require a tremendous amount of capital effort to start both a very large outcome study and two very large LDL trials, BROOKLYN and BROADWAY, based on FDA feedback for the LDL indication. That's the indication that all other LDL drugs have achieved prior to outcome data. And we started those trials at the same time as the MACE indication, which is the PREVAIL trial. So, the, again, BROADWAY and PREVAIL—BROADWAY and BROOKLYN have finished and will start reading out, and BROOKLYN's... We're finishing those trials, and they'll be starting reading out the results in the third and fourth quarter. And then PREVAIL, fully enrolled now, will read out a minimum of 30 months after April of this year. So here's the baseline data, and again, not only we were very gratified by enrolling the trials on time and achieving regulatory hurdles for China, Japan, Europe, and the United States, no easy feat, because each regulatory area had different requirements of patients and so forth, and we had to match standard of care. You know, the FDA wanted high-intensity statins. They don't use high-intensity statins in China. So it was just a monumental achievement to make sure that we hit all the criteria that all these regulatory bodies were seeking for approval. And we are also very pleased by the quality of the patients that were enrolled, as well as the baseline demographic data and LDL levels, because the higher the LDL levels, the better we believe the results will be with our drug. So 122 is the baseline for the patients with familial hypercholesterolemia, the BROOKLYN trial. 51% are on ezetimibe, which we think is a good thing. You know, we'll show you data again, that ezetimibe seems to enhance the effects of obicetrapib. 16% are on PCSK9 inhibitors. We know from genetic data, there is, there are additive between CETP loss of function and PCSK9 loss of function. So we believe, those patients should achieve a very significant benefit with obicetrapib on top of really ideal standard of care for those with familial hypercholesterolemia, ApoB 107, and triglycerides a little on the higher end of things. So we're very, very, very pleased with the baseline data for this trial. Then for BROADWAY, similarly, this is atherosclerotic cardiovascular disease patient population. This is one of the highest baseline LDLs for this type of trial, 98 milligrams per deciliter, non-HDL 125 mg/dl, ApoB 92. Again, standard of care, 65% on high-intensity statins, 26% on ezetimibe, some on PCSK9 inhibitors. And what we've been very pleased with both trials have been very little dropouts or very little drop-ins. Again, to the strength of the team, and how great quality we have on all our metrics for how well these studies have been conducted. And I also want to share with you, just briefly, we talked about this through a press release, but never really publicly, you know, what we found in our proof of concept Alzheimer's trial. And we went to a very distinguished Alzheimer's advisory board to discuss this data, and what we found, you know, for the first time with any therapy, reductions in what's called, hydroxycholesterol in the in the CSF. the plasma, we see that with statins, but in the CSF, statins have no impact on the hydroxy sterols, 24 and 27, which are linked to the pathology of Alzheimer's disease. The belief is that these sterols start the whole inflammatory cascade, which then leads to amyloid and tau deposition. Regarding the... These are all ApoE4 patients, either E3 or E3, four or four four, and we saw these results across the board. These are all highly statistically significant reductions in these hydroxy sterols. And regarding biomarkers, it was an open-label study, so it's maybe a little bit hard to interpret directly, but in a population, especially ApoE4, that already have mild cognitive impairment, you'd expect to see these biomarkers of tau and amyloid increasing significantly in six months. They were basically flat. And one biomarker, which lecanemab used as its, you know, primary efficacy parameter, the Aβ 40/42 ratio, you know, went up in the plasma, which is a positive sign, went up in six months, which was also significant. So we are encouraged by these reductions in hydroxycholesterol and the biomarker changes. What we decided to do, as much as I wanted to jump to phase III, we decided to look at BROADWAY data. We'll have a large cohort of patients with ApoE4 in the BROADWAY trial. Many of them are older, and you can use p-tau levels 217, 181 to, you know, diagnose pre-Alzheimer's MCI, and we can look at changes over a year compared to placebo with those plasma biomarkers. that may give us a confirmation of this pilot data, as well as then set the stage for further clinical trials to evaluate this endpoint. As part of our background science, we've commissioned and received many supportive data on genomics, loss-of-function CETP associated with lower risk of Alzheimer's disease, Lewy Body Dementia, Parkinson's dementia, in the setting of ApoE4, as we have animal data also confirming that, when you knock in CETP and use a CETP inhibitor, you delay Alzheimer’s disease pathology in these models. So we believe this is a very efficient way of using our capital to confirm this potential benefit in the BROADWAY trial. In PREVAIL, again, I cannot emphasize how pleased we are by not just enrolling on schedule at 1/3 the cost of most other CV outcome studies with a small biotech team. We gave the CEO award last night to all our clinical ops team for this reason. They really came through. Baseline LDL, 103. Again, one of the highest baseline LDLs for an ASCVD population. Non-HDL, 133, ApoB, 97, and when you saw the modeling that I showed you earlier, BROADWAY results can be used to model with this baseline data, what might be the expected relative risk reduction in PREVAIL. And we've again, we've designed it to maximize success. We don't want the trial to fail the drug. You know, the drug may not work, which is always the case with any novel therapy, but we wanna make sure the trial itself does not fail the drug, and we're very, very pleased with what we have for our baseline data. And then TANDEM is our pivotal trial for the fixed-dose combination. Ezetimibe alone, obicetrapib alone, the fixed-dose combination and placebo. This study was started with our partner at the Cleveland Clinic. They've done an exceptionally great job. Enrollment is going rapidly, and we are potentially ahead of schedule on this trial, with read out expected in the first quarter of 2025. So this is an LDL trial that will be allowing us to file the monotherapy and the fixed-dose combination at the same time, and what we plan to launch both drugs at the same time for LDL-C lowering. So that's our update. And as I mentioned to you, as a science-based company, you know, we, John and I, have been... We thought we knew a lot going in, and we've learned a lot more over the last several months about this field and area, and no one better to talk about it than John. And he can, I think, convey to you some of the great science we've developed at NewAmsterdam Pharma. So I'll turn it over to you, John. Thank you. Thanks, Michael. Michael has shown you that we are a company that's steeped in clinical excellence, but we're also marinated in science. We thought when we first looked at this drug, and Michael wanted to become the CEO of NewAmsterdam Pharma, that we knew everything there was to know about CETP inhibition and specifically about this drug. We had seen the phase I results from Japan, seen the phase I results from London, and we thought, "Well, this is it. The drug lowers LDL, it does it very well, and that's it." Well, I can tell you that that's definitely not it. There is much more to this mechanism than I ever knew before, and that actually most scientists knew before. There's also much more outside of the world of LDL lowering. So I think it's safe to say that this is not simply an LDL-lowering drug, and NewAmsterdam is not simply a company that's developing another LDL-lowering drug. That would really doing short to all of our, all of our teams. So I'm not gonna read this, but. And I'll go a little faster. So first of all, I would like to share the Lp results. Lipoprotein is on everybody's mind. Amgen is developing one, Eli Lilly, Ionis, Novartis has acquired the Ionis compound, Silence Therapeutics. Everybody is mostly based, and there's an oral Lp lowering molecule of of Eli Lilly. Everybody has either an RNA-based therapy or an oral molecule to lower Lp. And why would that be a good idea? Well, that's because of the middle graph. As you can see, the relation between Lp and risk is completely linear. There's a very clear hazard ratio of 1 mg around 30 mg/dl. I'm sorry, it's not in nanomoles yet. I'm still, you know, used to the European way of thinking in milligrams per deciliter. So anything above 30 mg per deciliter for lipoprotein little a is associated with an increased risk for heart attacks, strokes, aortic stenosis, and it's, it's a terrible risk factor. So if you look at the numbers of people that have this abnormality, they are beyond anything that, that you and I have ever seen. The, the estimated prevalence in the U.S. is something like 320 million, and globally it's about seven— so there are many, many people with this risk factor that, until now, could basically not be treated. So it's important for a drug to have an effect on lipoprotein little a, there's no doubt, no doubt about it. But the distribution in the population of lipoprotein(a) levels is very abnormal because it's not Gaussian, it's not normally distributed. What you see here in blue is the majority of the population have a completely normal or either basically zero Lp(a). So that's interesting because that means that Lp(a) has no function. You can live till 80 or 100 without Lp(a). In fact, many people do that, and that's good because that means that if you start treating it, you don't have to be afraid that you're gonna lower it too low, because there are many, many people that have no Lp(a) at all. And then in brown, you see the risk here at 30 increasing till about 80, and that's where this huge tail goes. It says 200, but I've seen people with 1,500 in my clinic in Amsterdam, and even 2,500. So there is this very long tail at the upper end of the distribution, where there's enormous risk. Risk for thrombotic risk in children and teenagers, early aortic stenosis, and everything. Now, the trials of our colleagues or competitors, whatever you want to call them, actually concentrate on the area above 60 and 70. That's where the entry starts in the HORIZON trial, in the Amgen trial, in all the trials. And that is very interesting because that means that the area between 30 and 80, there's no one in the trial for that. But what's true for above 80 will be true also for between 30 and 80, and this area is very large. There are many people with Lp(a) levels between 30 and 80. They have, let's say, mid risk. It's not this extreme risk, but they have mid risk, and that's where our drug could be very important for. Because I'm sure that the reimbursement agencies will say, "Listen, we will reimburse an Lp(a)-lowering agent for the same patient that went into the trial." If your Lp(a) is above 80 and you've had early heart attack, then, then, then I think treatment... But in that, in that gray area below, where there are many people, the story is somewhat different. So how could our drug be of help in that area? Well, the most honest thing a scientist can do is to show a waterfall plot. There's, because waterfall plots are every bar is a single patient, zero is the baseline, so there's no lying. This is not like, let's look at placebo and then subtract another 10%, then add it, that sort of stuff. This is total honesty. You can simply look. And this is what our drug did, actually in our ROSE and ROSE2. So this is two reasonably sized phase II trials, 12-week trials. So this is no longer a single little trial in 30 people. This is adequate numbers, and you can see actually that more than 50% of patients achieved a reduction of more than 60% in Lp(a), and some lucky guys actually got much lower. So also, this distribution is not normally distributed. This, as you can see immediately, that some people, and we have no, no idea why, have a massive effect on Lp(a) and some people have less. But in fact, if you add it all up, it is somewhere around 50%. So the median difference for the two trials is 57.2%-0.1%. That is a very robust Lp(a)-lowering effect that is much bigger than any oral drug or compound that we've been exposed to, and you'll see that here. So what I've put on a slide here, these are the PCSK9 monoclonal antibodies, previous CETPs, nicotinic acid, inclisiran, ezetimibe, tiny increase or no effect. Some trials show a tiny increase, other trials show no effect, so it's very hard to say whether it's exactly zero. And statins add a few percent to Lp(a), probably because of competition for the LDL receptor. But Obie, as you can see, has a much bigger effect. Why would we do this? There's one study by the University of Pennsylvania, Dan Rader, who've done stable isotope studies, turnover studies, and there you look at two things. You look at the synthetic rate, SR, or the fractional catabolic rate, FCR. Meaning that if SR is down, your - the synthesis of the particle is down, and if FCR is up, then actually the removal of the particles is up. Well, removal of particles was not up at all. The whole effect of anacetrapib, the other CETP inhibitor from Merck, showed a decrease in synthetic rate. So somehow it seems that CETP inhibitors have an effect like RNA-based therapies on the synthetic rate of the protein part of the particle, Apo(a).... So of course, for us, a very important moment will be next year when the HORIZON trial reads out. I think Novartis has said that it's going to be, like, in the second half of next year, because that trial will show, like, what we know for LDL. Is it the absolute difference in Lp that drives the benefit? Do you need to get to a certain goal in order to get the benefit, or is it a percentual difference? And what is the minimum amount of Lp you need to lower in order- We will know all that, so we can use that trial and then translate the trial results to our data. By that time, we will have Lp data in BROADWAY, and so we can then translate that effect also, like we can do for LDL and non-HDL, into PREVAIL. And that is, for us, a very important moment because it'll give our prediction much greater precision, I would say. So that is the important moment for us next year. Now, there have been always questions as to how, I mean, the Lp, there was now a stable isotope study by Dan Rader, which is greatly respected in humans, so that mechanism is done, sealed, and delivered. But how does CETP inhibition or obicetrapib lower LDL cholesterol? There is a study currently running, actually, again, at the University of Pennsylvania by Dan Rader, where he's going to do the same FCR and synthetic rate for LDL cholesterol. And I think I can tell you that the last patient was just randomized into that trial. So that's another clinical excellence, but then from another institute. And actually, so the entire cohort is now randomized into the trial, and now we simply need to finish the trial before we can show the results. But if you really want to do stuff like expression of LDL receptors, you need a mouse. You can't liver puncture a human being after 12 weeks to understand the mechanism of a drug. And so that's what we did in collaboration with the University of Leiden, where they have the most relevant mouse model for atherosclerosis across the entire planet, which is the ApoE*3- Leiden CETP knock-in mouse, and I won't bore you too much with the science, but that mouse model has seen every lipid-lowering drug. So it has seen all the monoclonals, nicotinic acid, all the fibrates, all the statins, and it predicted precisely what was seen in the trials later on. What you do is you give here, and here we were not only interested in the mechanism of obicetrapib per se, but also the mechanism of obicetrapib plus ezetimibe, because we saw in the clinical trials a larger effect on LDL than we had expected. So we wanted to understand at the mouse level what that actually means. Now, again, I won't bore you with the design. You, you give the mouse cholesterol and a Western diet, and at the end, you kill them. And then you basically look at every tissue. That's, that's what it comes down to, most mice studies. I'm not a mice doctor, but the results are interesting. So here on the left-hand side, red is obicetrapib, green is ezetimibe, and blue is obicetrapib plus ezetimibe. The left panel is CETP activity. After four weeks, there is no CETP activity left in the obicetrapib arm, neither at eight weeks. This was done to mimic the human situation. Our drug, at 10 mg, inhibits CETP activity by 97%. You cannot discern 197% in a mouse, of course, but it basically wipes out CETP activity. If you go to the left, these mice people are able to titrate the dose of the drugs they give to mimic the effect on LDL that we see in the humans. You can see here very clearly, this is the effect, obicetrapib alone, ezetimibe alone in green, less efficacious, and then the combo, very efficacious LDL lowering. That, that is already there at four weeks, and then six, and then eight. So this is exactly what you need because you can't study a mechanism in an animal model that has very different levels in terms of LDL than a human, of course. This was exactly what we wanted to happen. Then what you do is disappearance curves. So you look at the disappearance of LDL particles, and then you see the mechanism of CETP inhibition is simply to remove LDL particles. So it is exactly the same mechanism for statins, ezetimibe, PCSK9 monoclonals, and bempedoic acid. And what you can see, and which I'm very excited about, is the blue curve, that is ezetimibe plus obicetrapib, is by far the most potent combo to remove these particles. And that is exactly the bucket of sand that Michael was talking about. You want to get rid of the particles, not so much of the cholesterol. You want to get rid of the particles, and the combo does a great job, as you can see here on the slide. Why is that? Well, the answer is extremely simple. This is LDL receptor expression on hepatocytes, and you can see here that Obie on itself already increases this very statistically significantly so. Ezetimibe does it, but it, this just doesn't reach statistical significance because of the number of mice per cohort, but the combo does it, too, and better than the mono. So with this, we also satisfied the FDA, that wanted to know that our mechanism of action for lowering LDL is not based on inhibiting the production of LDL... which would be totally different from any other drug, would be mipomersen-like, and you don't want to look like mipomersen, I can tell you. I was involved in the early trials. So you want to be like statins, ezetimibe, bempedoic acid, and PCSK9 monoclonals, and did prove—this proves it. So now the only thing we now need is Dan Rader's trial to confirm this, which, by the way, is already done for anacetrapib, another CETP inhibitor, so we're not expecting any miracles there or any unexpected things. So this slide sums it all up, and just look at the blue little box here, increase in hepatic LDL receptors that decrease plasma LDL levels. So with this science, we've kind of finished this chapter in a very long discussion, where people always said, "You'll still read papers where people say, 'We are not going to put any CETP inhibitor trials in with the meta-analysis because their mechanism is very differently.'" Well, that is nonsense. The mechanism, in fact, is exactly the same. I already highlighted shortly the Obie plus ezetimibe combination. Now, bear with me. So in the mice, this is ezetimibe alone, Obie alone, and this is Obie plus ezetimibe. This difference is 49%, and Obie mono is 28. This is ROSE2. This is Obie plus ezetimibe. This difference is 34%, and this is OCEAN. Here you go, ezetimibe alone, 15, and the combo has a difference of 30. All these numbers, 49, 34, and 30, are way more than just ezetimibe, which never gives you more than about 15%-18% additional LDL lowering. So we are convinced that there is a synergistic effect, and I've heard it called the Entresto of lipids. One plus one is more than two. It's in fact, three. The reason for that, and we are busy proving that in mice models, is that, and we have initial data, so I'm not getting this out of my sleeve, is that Obie pushes cholesterol into the intestinal lumen, and there, ezetimibe blocks its reabsorption. So you have it coming from one side, blocking it from the other, and that's, that's the biological basis for this, for this, interaction. And here, I'll show it to you again. Here we are, cross-trial comparisons. So if you go from ezetimibe, baseline, Simva-- Sorry, ezetimibe. Simvastatin, 36%. You add ezetimibe, the additional lowering you get is 18. This is bempedoic acid, baseline, 17%. You add ezetimibe, an additional 16%. In our trials, you get about a 40% lowering for- from baseline for Obie-ten, and then the 34.4 for ezetimibe. Clearly and statistically, a very different additional benefit. That's why we have such great hopes that this will be a wonderful combination therapy for people that really need LDL lowering. Now, all of this is totally moot if it doesn't translate into athero data, and of course, athero data, we need human trials. But we wanted to make kind of an entry into the human trials by again going to the University of Leiden and studying the same mice model, and now for athero. These are unpublished data that we've never shared yet with anyone. We have the same design. What's very interesting is that in mice, you can actually, because you sacrifice them, you can look at plaque functioning, so Type I, Type II, Type III, Type IV, and Type V severe plaque. So in these mice, they can very diligently determine how severe the plaques are, and then basically you give them, you know, obicetrapib and ezetimibe, et cetera, et cetera. So the first thing you need to know, are the drugs doing to LDL or non-HDL what they're doing to humans? And they do. Look again, this is Obie alone, very low non-HDL, and this is the combination. So this is Obie alone, ezetimibe alone, and the combination exactly as you see in humans. And also, the percentage decreases are the same for this mice model as they are for the human situation. And then you look at the lesion area. Now, this is an amazing slide to watch because I have seen many, many, many of these slides from many, many other drugs. Now, bear with me. Go to the first slide. This is the control. This is total lesion area. So this is surface of atherosclerosis across the aorta, the aortic root, and the coronaries, and the valves in these mice. And what you can see is that Obie alone already has a massive effect. Ezetimibe has a reasonable effect, but the combo kind of wipes atherosclerosis completely from these mice. This effect size from gray to blue, I've never seen with any other drug that I've worked in the past. And so then the next question becomes: Is this an effect on overall atherosclerosis, or is this effect limited to certain plaque severities? And what you can then see is that by far, you only have to look here at this little blue thing here. This is severe lesions, Type IV to V. The biggest effect by far is on severe lesions.... And that is exactly what you want. It is clinically quite irrelevant to work on a tiny beginning lesion. You want it to work on advanced lesions because those are the ones that are gonna rupture, have a thrombosis, and then a heart attack or a stroke. So this is exactly what you want. You want a drug or a combination of drugs, like the fixed-dose combination of Obie and ezetimibe, that knocks athero out in general, but then mostly actually on the severe lesion here. Look at that little cross. Doesn't mean that all the mice are dead because everybody's dead here, but it means that this is a statistically significant difference with regards to this and that. So again, the synergy we observe for the lipids, we also observe for the athero and the severity of the athero. We wouldn't be NewAmsterdam if we wouldn't take this one step further. So mice are nice, we always say, but humans are really important. Now, this is a CT angio image. CT angio is becoming the standard of care in cardiology and in diagnostics for coronary disease. It's gonna outperform IVUS, coronary angiography, and it's non-invasive. You have a peripheral contrast injection, and then you do a CT scan of the chest. You can see soft plaque, you can see inflamed plaque, you can make an attenuation index of the pericoronary fat and everything. And so we have decided, and this is the first time we announced that, to do another trial, and that trial is called after one of my countrymen, Rembrandt. And Rembrandt, of course, was a master painter, and this is going to be a master trial because this trial is going to prove with CT angio that the fixed-dose combination. So this is a trial of just the fixed-dose combination against placebo over an 18-month period, that actually we have an effect on athero, which is important because cardiologists love images. So it's very important for cardiology that even if you've seen an outcome trial be positive, that you understand that the reason for that outcome trial being positive is, in fact, regression of plaque, as we've shown for atorvastatin, for rosuvastatin, for Repatha, and for all these other things. And I can tell you, and I'm proud to announce, that we've randomized our first patient in this trial yesterday. So this is another trial that we're doing that is big pharma work, but we're doing it as a small company, and we've already randomized. It's the last phase III trial, Doug, that we needed to have a patient randomized into. And so now you've seen the full width and breadth of our program that is yet to come. So on the right-hand on this slide, I think are the benefits of REMBRANDT. We have increased utilization of CT angio for diagnosis of cardiovascular disease. This will become the gold standard very soon, I think, for among the cardiology community. So we will have positive traction with positive cardiologists if we can show a positive trial. I think it's very intuitive that that's important. Also, this trial is designed to demonstrate the clinical benefit of the FDC because we don't have another phase III trial for the fixed-dose combination, so this will be the baby of the fixed-dose combination, because here we can show that we really have a profound effect, hopefully, of course, on athero. And at the end, there are some, I would say, vague rumors that imaging in the future might support regulatory filings. Where exactly in the file, I’m not an American, so Michael knows much more about the FDA than I do, but even in Europe, there are some considerations about that. So that is kind of more a hope than a certainty, but I think nevertheless, that that's important, too. Let me end with diabetes. Why do I bring this up on an R&D day? Well, three weeks ago, The Lancet published a manuscript that showed that high-intensity statin resulted in a 36% increased risk of new onset of diabetes. This number was much higher than previously understood. We always, Michael and I, used things like 10%, 15%, but especially... And we also did not really appreciate that the higher the statin dose, the greater the risk. And so this is huge numbers, 36%, meaning that any other drug that you use on top of a statins, if that drug could help in preventing that side effect, would actually be wonderful. Now, there's a meta-analysis in the European Heart Journal that shows that all previous CETP inhibitors had this protective effect, as Michael already alluded to, on the diabetes risk. And because one of them, dalcetrapib, had no effect on LDL whatsoever, the effect has to be through HDL. There's no other. You can't get around this. If a drug has the only effect that the drug has is on HDL cholesterol, and that drug protects against 2, type 2 diabetes, that is the intermediate biomarker. So we think, we postulate, and there's a lot of evidence for it that I'm not gonna bore you with is that increasing ApoA-I and HDL actually is anti-diabetic in many ways, at the muscle, at the, at the, at the liver level, at many, many levels. And so we, in fact, hope, of course, because we haven't demonstrated it, that we will see that effect both in BROADWAY, but more even more so in PREVAIL. Then I'll just shortly highlight the particle numbers. So everybody is talking about ApoB in scientific journals, but in fact, LDL particle numbers, as determined by NMR, are frequently tested in the United States, very frequently, either the Nightingale platform or the LipoScience platform. And what you can see is that if LDL is low, LDL cholesterol is low, but LDL particle numbers are high, you still have high risk. So it's again the bucket of sand. The more particles there are, it's the particles that drive the risk and nothing else. And so I'm proud to announce that, in fact, in ROSE, what you can see. So this is NMR profiling of our particles in this trial that was published in the Journal of Clinical Lipidology. This is total particles. This is Obie alone. This is Obie plus ezetimibe. Those numbers are already very impressive and better than any other lipid-lowering therapy, but look at the small particles. It's over 90%, and you can see that because LDL size goes up. So this speaks to a very differentiating feature of CETP inhibition. Statins, ezetimibe, and PCSK9 monoclonals preferentially lower large particles first. We actually lower all particles, but have a very big effect on small particles. So when you add that all up, and you look in row two, brown, monotherapy Obie, blue, the combo, you see a very consistent effect on the entire lipoprotein profile, ApoB, total particles, small particles, and small, dense LDL cholesterol. I won't go into that, but that is, that goes with the small particles. That's the cholesterol content of the small particles. So that tells us that when you're on a statin, the majority of your particles are small particles, so the residual risk that Michael was talking about is very likely determined to a large extent by the presence, remaining presence of small particles. And you can see that here. Look at the right-hand side at the ROSE results. This is placebo patients. So these patients are on high-intensity statins. Total LDL particles, about 1,000. 70% of those are small particles. That is not true in a normal situation. So the majority of the particles in a high-intensity statin to the patient is small particles, and LDL size is small, 20.3, should be above 20.5. If you then give Obie or the combination, look what happens to the small particles. They almost disappear. So now, actually, small particles are a tiny fraction of overall particles, and LDL size increases. So this is a very interesting effect because the current epidemic of heart disease is driven by the epidemic of insulin resistance and obesity. This profile is especially present in people with insulin resistance, type 2 diabetes, obesity, if they're and even more so if they're on a statin. So it's intuitive to be appreciative of a drug that is able to get rid of the small particles and the residual risk associated with that. Then I have three slides that I received two days ago. So this is totally unpublished data. So there is a whole lot of mediocre science out there that thinks that observational data for HDL cholesterol in with a follow-up of 5 years has any meaning. Now, we all know that alcoholism in the general population is the most important driver of high HDL levels. So in order to get rid of that confounding bias, you have to follow up patients for at least 20 years, because then all the people that are alcoholic are dead. And there are just two large studies that have done that. And in order to get rid of that confounding bias, you need to do cubic spline analysis. Brian Ference, the godfather of Mendelian randomization, has taken the UK Biobank and has done that cubic spline analysis for HDL cholesterol. And look with me at these data. This is HDL between 30 and 35. The risk over your entire lifespan, this is all-cause mortality. This is all-cause mortality, the most severe readout of anything that we have to offer in clinical medicine. Then you go down 40-45, 50-70, 75, 95-100, very high HDLs. There absolutely is no curve, linear or kind of U-shaped curve at all if you do this. Simply not there. Here, risk for MACE, exactly the same. So if you treat, if you have enough. So here, the number of patients is 500,000. The number of events is 30,000. So this is not. I mean, there's not much 95% confidence interval around these findings. Then it's very clear there absolutely is no U-shaped curve for HDL. That's important because our drug raises HDL. So what Brian also did in the next slide, is he took the REVEAL data. Remember, anacetrapib raised HDL cholesterol by 100%, and then he took the entire MedDRA database of REVEAL, all safety. So this is fatal events, fatal or non-fatal events, infection, cancers, anything, and he actually looked whether the HDL increase of 104% was related to any outcome in the MedDRA. Well, doesn't take a rocket scientist to appreciate that there's no risk. So not only is in observational Mendelian randomization data, there's no relation between high HDL and increased risk, but even if you increase HDL or double it, there's absolutely no relation with any safety outcome parameter. And so this, again, is important for us and for the regulators to understand that our HDL increase might not help reducing heart attacks and strokes, because we know that raising HDL cholesterol does not, but it's definitely not something that leads to any safety issue whatsoever. Thank you very much. Any questions from the audience before we take a short break? Ques- B.J. Oh, B.J., I'm sorry. I forgot. Yes, I get everyone's been waiting for this. We have B.J. now coming up to his debut to talk about the commercial story. B.J.? Hello, everyone. It's good to see you this morning. The one thing that I asked is if I could please not follow John. Very, very difficult act to follow. Can everyone hear me just fine? Okay, appreciate it. It's great to meet you all. I'm B.J. Jones, Chief Commercial Officer here at NewAmsterdam Pharma. I've been looking forward to having a chance to kind of engage you all and just talk through what our initial thinking is as it relates to the opportunity associated with Obie and essentially what our, what our plans are. As a brief introduction, frankly, I've been in this space, kind of in our industry, working in far longer than I want to admit. But I've been fortunate in that I've had the opportunity to really work for tremendous organizations, large pharma, medium pharma, as well as small biotech. And over the course of my career, I've been involved with really some major multibillion-dollar brands as well. And I've really had the fortune also to have a major leadership role in some significant launches. These on the left here are... It's not all-inclusive, but they're some of the major products that I've been involved with, specifically around blockbuster launches with Abilify, Pradaxa, Farxiga, and most recently, Nurtec ODT. And speaking of Nurtec ODT and my experience with Biohaven, and you'll, you'll hear me talk about this quite a bit today because I think there are a lot of similarities between essentially what is the story of the David versus Goliath, right, in the marketplace, and what was a distinguished and differential medication, in Nurtec ODT, but versus what was kind of this, this mammoth market opportunity. But, I remember sitting in front of many of you, and others, at Biohaven, having a dialogue and conversation in which many would say, and larger competitors would definitely say, is that, "Well, that's good data, and that, that's really good, but there's no way that Biohaven can do what's necessary to launch this drug. And, and so that's cute, Biohaven, that you think you can come up with a great thing, but you have to find a partner, or you have to find somebody else to make this happen." And, I can say with confidence and great pride, is that that was not necessary at all. And I would also say that there was a benefit, a differential benefit of being a smaller organization and could focus on what was necessary to not only compete but beat the larger pharmas that you see listed on the right-hand side there. So after our acquisition by Pfizer and the transition activities I was involved in, I was really had an opportunity, a unique opportunity to kind of sit back and say, "Well, what's next? What, what do I want to actually get involved in?" And there were a few kind of priorities that I thought about, one of which is I wanted to be involved with a unique, differentiated molecule, something that was not a fourth or fifth in class type thing, and would bring some type of incremental benefit, but something that was transformational. I also wanted to be involved in an organization, frankly, had the funding to do what's necessary to make sure we could reach as many patients as possible. And what was really important to me was the fit, the cultural fit, and the individuals that I work with. And I can say that, you know, we've been able to find exactly that here, in NewAmsterdam Pharma, and I believe this truly is what is an unprecedented opportunity. Look, you've just heard for the last hour how special and unique this molecule is. Obie is different, and it will make, if approved, a profound impact on patients, and that is why, frankly, we're all in the business of what it is that we do. We have a very bold ambition. We expect to transform treatment in this space. Clearly, it's necessary. You heard, you know, Michael talk earlier about the unmet need. We'll talk more about that, but we've got to change the dynamics of what's happening. There are too many people being lost, and it does not have to happen.... And then when you talk about, you know, the team, they're a dream team of experts. You've just heard from Michael and John, who literally sit on top of the Mount Rushmore, right, of lipids and CV, and you could not find better people to lead essentially what is this opportunity associated with here. And frankly, I learn something new every time I listen to both of them. So, I'm in the right place, and I'm very bullish about what the opportunity looks like going forward. So let's, let's talk about that. So first, maybe we talk just about the opportunity generally. And I'll say, you know, the LDL market is massive, no matter how you cut or look at it or slice and dice. But we'll start on the left-hand side and just say, generally, you know, with anchored data, right, and secondary data that basically says, U.S. only, 72 million folks that are diagnosed with hypercholesterolemia. There are approximately 10 million or so diagnosed patients that are not being treated with statin or LLT, and then there are approximately, they're north of 30 million or so, that are actually not at goal. So I would say, you know, the sweet spot, in some sense, basically says over 40 million patients are undertreated or not treated. That's the space that, that we go after, right? The low-hanging fruit in some sense. What that translates into is, as you see, approximately 250 million or so RXs annually, on an annual basis, and importantly, that number is growing. If we look at the next three boxes, basically, we're talking about the relative size of the market from a patient standpoint, but we see if you look overall at the broad market, we see there's greater than 4% growth over the last two years or so. If you strip out what are statins and just look at non-statin market, that's growing at actually a high teen rate. And then if you strip out ezetimibe from that and just look at branded, we're finally starting to see traction in that space. I'm not telling you anything you don't know. You guys have seen this data, I'm sure, but tremendous growth in that space. We expect this to continue. That's the marketplace that we're entering into. And so once again, there's a lot of, I'll call it tailwinds. Things are working in our favor, right, as we progress towards what would be, potential launch. So, but clearly, there's an issue, and there has been an issue, and let's, kind of face it head-on and just say, general success has been limited in the CV space. And this data was basically, captured and memorialized to, to just show that commercialization, specifically in, in CV therapies broadly, have had the lowest proportion of launches that met or exceeded expectations. And there are some hindrances, right, and some challenges in this space versus some of the other, areas, and, and also setting very, very high expectations could be, you know, a balance of, of some of those conditions. But I'll say specifically as it relates to the LLT market, like, why haven't we seen more success out there? And it's multifactorial. Obviously, there's a lot of layers to this onion, but I would suggest that there are four primary areas, and it's outlined here, and you can see it kind of in two categories, one of which is product-specific related, and the other is more around basically an execution element, around what happens in launch excellence. So we'll spend a little time in each of these areas, but the first of which is just poor product differentiation, or where new products are actually coming to market, but there are gaps, right? Those gaps are a big challenge for them in the marketplace. Understanding the market or perhaps misunderstanding the market around where the opportunity exists and how to penetrate that opportunity. Limited market access, this is not clearly just an LLT issue. It's across any launch in the branded space. And then what I'd call low prioritization or underinvestment. But I can tell you with confidence is that NewAmsterdam and Obie specifically address each of these head-on. So let's talk about each. So the first of which is I'll call poor product differentiation, and I'll say at launch, 'cause I think that's an important asterisk, and I won't— You've just heard for the last hour of why Obie is so differentiated, why we believe this is really a difference maker in the marketplace overall. But I can say that, look, Obie and the FDC basically check all the marks, right, that are necessary. In the primary market research that we've done, we had a big demand study we did of over 250 clinicians, and in that demand study, we basically teed up what was our target product profile or TPP. We did it based upon what's currently in market, and we did it versus what we believe to be coming in the pipeline as well. I can tell you that tremendous receptivity to what they truly perceive as very differentiated from the rest of the marketplace and what that offering is, and their relative belief in just how much of the market that Obie will demand, if approved. And again, we've talked about all the, the special sauce in some senses off on the right-hand side for Obie specifically, but the key piece is that if approved, Obie will be the first high-efficacy oral LLT since statins, and you heard John mention that before. It's a fundamental differentiator for us. Number two, understanding what I'll call the evolving market or so. And listen, there have been a lot of changes, a lot of shifts that have happened, frankly, since the launch of even PCSK9s. It's been many years now. We're finally starting to get traction, but there are reasons behind that. That evolution has actually increased the understanding, I think, of what has been this mammoth unmet need. It's increased demand and broadened what is that prescribing base, and there's a real opportunity for us differentially there. It's increased because of awareness, better awareness, at least, of LDL goals that Michael mentioned earlier. Accelerated adoption of these treatments beyond statins, that's all gonna work into our favor. And then Obie may be attractive to a broader segment of the marketplace, not just specialists, but certainly primary care, especially when you look at our profile, one might even say, and we heard this in, in a lot of our primary research, is it's kind of the perfect primary care drug in some sense, because it's simple, it's high efficacy, and it's safe. And so on the right-hand side, this is a key piece from our strategy, right? Is that we will target specialists and primary care. 'Cause if you just look at the data here, it suggests that the vast amount of patients, that's where they sit. They sit in the primary care space. That's who they're seeing on a daily basis. And what was a bit surprising, frankly, for me, not so much on the primary prevention side, but even looking at secondary prevention, especially high-risk ASCVD patients, still, the vast majority of them are actually sitting in primary care offices. And so we can't not avoid that and expect to get to the patients who need this the most. And so we'll make sure that we target that in an effective way, not the entire primary care market, but we'll do it in an efficient manner, where we get to the highest volume writers. Number three, again, this is not a surprise to anyone. It's limited market access, for sure, but here are some of the things that are starting to shift over time to kind of shift to our favor, and Michael mentioned this up front, is that recent guideline and label expansion. So guidelines did change with ACC to start target goals. We're kind of catching up with the Europeans in this space. And then, just recently, FDA highlighted the need to reduce access restriction for LLT specifically, which is why they started to make some changes in labels. That will all, we believe, work to our benefit as well. Increased payer and patient access, and we reflect—that's reflected in PCSK9s, initially kind of resetting the price, made a huge mistake initially, but it was tough for them to kind of dig themselves out of that as well, even after they dropped their pricing. Broader labels, we believe, will translate to broader access, and then payers now are in a space where they're paying, right, for this. And I think the key is on the right-hand side there, where we're starting now, Repatha now has broad access and about 92% coverage. Not all similar coverage, right? Some better than others, but. And that has led to what has been, you know, more traction in the space and doing even better. And we believe that our anticipated value proposition, again, differentiated value proposition, is expected to accelerate demand and payer access. When we drive that demand, when we drive that top line, it will impact payers' willingness and ability to, frankly, put us on formulary. And then lastly, in this space, I'll say, look, PCSK9s were differentiated. They brought kind of a new type of efficacy in this space for sure, but the route of administration was a challenge for them, right? It limited, you know, uptake and early adoption. Another recent oral non-statin LLT executed what we all, I think, believe would be a suboptimal launch, and there's questionable differentiation, right? So again, there are benefits, right, from... But there were gaps, right? And those gaps made a very big difference in the marketplace. Initial promotion and sales force issues out of the gate. Certainly, COVID did not help at all, but it muted launch uptake in that space. And then I think this is really important, is that primary focus from all of those launches were really more around what is the traditional launch plans, traditional launch, execution, with really what was necessary was more of a modern launch, and that is the approach that we will take to have a 360-degree kind of promotional engagement. They'll be high in the omni-channel space, and we can be very, very targeted in that regard, and therefore, get greater return on all of our efforts. So let me maybe take a couple of minutes and walk you through a couple of case studies that I think are very relevant for us. The first of which is oral anticoagulation market. Again, we have to go back a few years, but it is the CV space, so it's, I think it's relevant to us. And, to set the stage and remind you, especially for younger folks, right, who weren't here at that point in time, I was at BI. I was sitting in the launch team for Pradaxa, and we're talking about Coumadin, again, which had been kind of the only tool available for 50 years or so, and then we introduced what was this new space. And not only was it new, but there was an entire infrastructure set up around Coumadin, like Coumadin clinics. So there was, like, even financial incentives of clinicians to stay with what was the older medication. I think this is not the only example, of course, but it's a perfect example of how when a new product with a differentiated benefit actually comes to market, one, payers will pay, and importantly, prescribers will write. And you see, as Pradaxa entered, and Xarelto, and then Eliquis, it's been nothing but what has been a very strong, you know, launch curve to this day, where Eliquis is still growing at double-digit rates year-over-year. So that's extremely important. And then, of course, what happens to the market share of warfarin and Coumadin declines, and it declines dramatically. There's also another case study I like to use, where basically it's a very similar kind of market penetration. This one was a bit more unique, where it's mandated primarily by what had been generics as well, but the entrance of this new MOA started with injectable mAbs... and then translated to a similar MOA, but orals in the space. Indeed, this was more recent, but, the branded medications were able to penetrate 25% of that generic market within the first five years or so. In that example is migraine, and obviously, I'm very familiar with this. Just walked away from, you know, watching all of this take place, being a part of it, understanding what, what was the key trigger and why it is we were able to grow so quickly in that space. The other thing that's very important here, and this is relevant for us as well here at NewAmsterdam, is that oral CGRPs rapidly overtook injectables in volume and share. Yes, the, the, CGRP mAbs got off to a great start because it was new and differentiated in the space, and there was an unmet need. But then in addition to that, when orals jumped in, we saw the flattening and then declining of those mAbs as the preferred route of administration is oral. And I think that's. It's kind of a given, but sometimes that's. I think that's lost on folks, but you see it here playing out in a real way. I'd also say if we go back, maybe case study number three, let's go back to NOAC market to just talk about market value. In this one, of course, from a dynamic standpoint, we saw what is basically not just kind of a switch from generic to branded, but we actually saw an overall growth in the market of overall, from a volume standpoint, of 75%, very important. Key point as well, though, however, is the value of the market grew dramatically, 43x the value now as we're shifting from what is generic to branded. So very key. Again, this is not the only example. There are many examples like this, but it's kind of that time frame where you're looking at a marketplace where there's tremendous unmet need, and there's what is a new kind of solution that delivers against whatever there's not been able to do. This is the type of tipping point I think that we're walking into with Obie. The other bottom line here, which is really important to recognize, is that both those cases are a scenario in which we're looking at switch markets, meaning literally that for utilization of the new branded, it means you actually had to displace the generic. It's a major change in prescribing behavior, obviously. Our ask, as we've talked about, is not to displace, is to add on top of the statin. So we're not asking them to change that dramatically in some sense, but keep using your statin, please, and oh, by the way, put this on top, and now we can help to reduce by 50% or more, depending upon the mono or the FDC. So much easier to take place, and the dynamic and what we're asking for this change, right, is even simpler than those other examples we showed. So then what? So what, B.J., what's happening? And I would say that the marching orders are very clear for us from a commercial and medical affairs standpoint. The mission is to transform the health of folks living with CVD. Our objective is to maximize the value, obviously, of the organization and the product itself, and we do that primarily in three different ways. I'm sure it's not the first time you've heard this, but we're focusing on each of these in parallel. Got to make it all happen, but first is to prepare the company. And you've heard from Michael and from John, and you've seen the evidence of the great work that—what Doug and his team have been doing from a clinical standpoint. This organization was built around clinical and development excellence. Excellence. Now it's time for the organization to grow and to evolve, and we need to have the same standard on the commercial side of the business, and that's exactly what we're doing, is preparing the organization from a capability standpoint, to be able to deliver the same way my colleagues have for the last few years or so, and we're, we're actively doing that. The other thing that we're responsible for is preparing the market, and that's making sure that the market is aware, they understand and believe in NewAmsterdam and in Obie specifically, and just educating on the unmet need. So again, people recognize something must be done, and then we will deliver what is the solution to make that happen. And then lastly, it's my colleagues, you know, behind the scenes at this point in time, but the marketers are working on really understanding the insights, making sure we understand what's happening in the marketplace. We know exactly what to target, what manner to target that in, how to get the greatest return, and we will create what is a modern and innovative go-to-market model that allows us to differentially impact the marketplace and launch. So with that, you know, I think we're poised for success for all the reasons we've discussed, like certainly clinical excellence. I would suggest to you all that it is a benefit to be a smaller organization. It's proven at Biohaven to be a smaller organization, more nimble, able actually to do more with less and to be successful in that space. The commercial launch team, I'm incredibly blessed to have very just top-notch talent that you, you won't find better talent in the industry. And not only did was I able to bring over, you know, a lot of my colleagues from Biohaven, who have recently set the standard for modern launch, but in addition, I'm working with talented individuals who've been a part of billion-dollar brand launches, including statins and ezetimibe. So there's a lot of deep expertise specifically in this space on the team as well. And then I guarantee you, we will continue to focus on what is innovation at launch, making sure that we can impact the marketplace in a differential manner than what you've seen heretofore. And I think we're off to a very strong start. You know, I feel very confident about the approach. We are very proud to say we just launched and deployed our MSL team, so they're out in market at this moment, engaging with KOLs across the nation. Again, communicating specifically around what is the broader unmet need, but also getting people prepared for what is coming with Obie and the data that's on the horizon as well. We're building broader awareness and targeting HCPs to help them understand we need to improve kind of the Z state and exactly what the issues are and how we can address that and change what is that horrible number that Michael started with around CV death. And we're generating awareness and enthusiasm. And I was talking about one of with one of you earlier, just about, we have all this great data that's gonna start coming out in 2024, so we're excited. It's a big year, but it's not just good enough for us to be excited and frankly, for you all to be excited, but we need to make sure that the marketplace, the KOLs, prescribers, are actually anticipating, right? And they're excited about the data that's actually coming, because it's going to be great data. We believe that, but we don't want it to land with a thud. So we wanna make sure that people are receptive and waiting for that. We're cultivating very strong relationships with patient advocacy groups to make sure we can partner with them, you know, across the industry, to make sure we're doing what's right for patients. And we're gaining deep insights and partnering on specific initiatives that, that work for us. We're gonna continue to elevate the corporate profile, and our public relations plan is very broad and comprehensive. Hopefully, you all are witnessing this as well. Then, lastly, and certainly not least, is enabling access, and we believe that launching with expected MACE data will help us accelerate what would be approval and the breadth of launch. Right now, we are engaging in a very productive manner, actually, with payers, key decision makers in this payer space with a pre-approval information or PI deck. Okay? So lastly, and I'll close on this, and I believe we're gonna have a bit of a Q&A, but if you have heard nothing else or remember nothing else, please remember this, guys: we are setting the stage for what we believe is a transformational launch with obicetrapib, a differentiated product for all the reasons you heard of before, is going to deliver, you know, in our phase III studies, and this will be a different solution for the marketplace, and we'll make sure people understand all of that. The key understanding of the market and patient needs, again, there's an evolution that's been happening in this marketplace. I believe, you know, those things are shifting in our directions. They're tailwinds versus what were headwinds for some of our competitors or some of the other folks in the space earlier. We know accelerating market access, and that's like apple pie. I get it, right? But we know that's a key focus for us. We will make sure that we are focused 100% on making sure that we're creating essentially what would be a frictionless access, right to trial. That's necessary. When a doctor writes a prescription, it's got to go to that patient. They have to be able to go to pharmacy and fill that and pull it through. We'll make sure that we provide that support as we continually kind of get broader and broader access. And then lastly, and importantly, we're gonna invest to win. And what that does not mean is we do not need to invest and spend like Big Pharma, and we don't need the numbers that Big Pharma does either. We can be very focused, very efficient. We can do this in a manner that allows us to do more with less. I think we set the model for that at Biohaven, and we're gonna pull through what were those learnings of best practices, and frankly, a lot of mistakes that were made as well. We've learned from those as well. We are, as you might imagine, and might anticipate, I'm very bullish about the future and what the opportunity is for us. Appreciate your time today. Thanks, everybody. And Michael? John, anything else? Sure. So yeah. So now we have time for questions. A lot of questions. Okay, Dennis, I'll start with you. ... Oh, wait for the microphones. Okay. Dennis, right there. Yeah, I``ll start. Hi, good morning. My name is Dennis from Jefferies. Two questions, if I may. I appreciate going to the phase III LDL reduction data in the second half. People have mostly focused on the 12-week data, but I'm just curious around your base case expectations for the 52-week data, and how could that impact your confidence for PREVAIL? Sure. I'll let John comment, too, but we, you know, we don't expect to see much of a diminution of effects. I mean, we looked at all the other, like, 52-week trials, like with... You know, take bempedoic acid, for example. I think it was like 18%. I think it went to 15% at week 52. And we have anacetrapib data, you know, from all the longer-term trials. There's really no decrease in efficacy at 52 weeks. So we've been—like I said, we're very encour— We— You never know till you get the data, but what we can say is we've had very, very little dropouts and very little drop-ins throughout the entire trial. and so, we feel that we're expecting very little impact between week 12, the primary endpoint, and week 52. And we are committed to showing both, and we have our release of the data just to make sure we can alleviate any concerns people have about the prolonged effect. One point I just wanna make about the... You know, we have a press release. We'll have the data press release. We are working with very well-established, prominent academic institutions, which have committed us to be, you know, pretty minimalist of what we can say to avoid any effect on publication. So we have restrictions on that. We don't want any way affect the New England Journal, whatever the publication is in the future, and so we will do our best we can to make sure that we get that important data out, and then as soon as we can get things published, and this team, we do work very quickly. We're gonna get all the data out as fast as we can at medical meetings and so forth, and that's our commitment. But as far as the press release, initially, we might be limited in what we can say other than the primary endpoint and in general, safety. ... I think also what you have to realize is that at the 12-week mark, there usually doesn't happen anything to placebo. So that usually is flat, and then, so what you see is the actual effect of the drug in the treatment arm from baseline, which will look a lot like the phase II, by definition. If you go out in time, there will be people that are not that adherent, so you'll have a little less of an efficacy, but the placebo will go up, almost always in lipid-lowering trials. And just like 3%-4% going up, means that that differential will probably stay very much the same. So that's why, for example, in the anacetrapib trials, they are easily more easily comparable to our trials because there is REVEAL in FH, which was a year, exactly like BROOKLYN. There's DEFINE, which was even an 18-month trial, and REVEAL, we had four years—sorry, yeah, REVEAL, four years and six and a half years. And so there was not much attenuation over time when you do a placebo-controlled analysis. And that is—You have to bear in mind that also for the MACE outcomes in, in an outcome trial, there's always an increase in the, in the LDL, in the placebo arm, and so it is truly the placebo-corrected benefit that you have to look for. Okay, got it. That's very helpful. And maybe as a follow-up, a question for, for B.J. on commercial. Like, if you fast-forward a couple of years and, you know, you have, Obie approved, as well as the fixed-dose combo, is there any sort of prioritization between those two compounds, and how do, IP and the IRA impact that decision? Thank you. Good question. I'd say just generally that, the relative priority, I would say, is balanced, will be based upon the needs of the customer set. So at the outset, as you might imagine, with some of the primary research that we've done, we've actually seen that, you know, specialists might index more heavily towards the FDC, primary care, more indexed towards the mono. But our expectations is it's probably going to be about 50/50, I think, generally, you know, across. And so—but it will be based upon what are the patient segments and what's the relative need in that space. So I don't see any issue with that. As it relates to, you know, going forward and IRA and all of that, the benefit is that we break up essentially what, you know, is that overall revenue, you know, between the two, which is a benefit, you know, for us, for sure. So I think it works to our benefit. Works to the broader marketplace and patients' benefit, but ours as well from a business standpoint. I guess Tyler has the mic, right? Great. Thanks. Tyler Van Buren from TD Cowen. Thank you very much for the excellent presentations this morning. The first one is for the BROADWAY readout in Q4. Regarding Alzheimer's, what change in OH, in tau 181 or 217 levels do you need to gain confidence to move forward and potentially start the phase III that you want, Michael? And the second one is another one for B.J. as well. Can you compare and contrast what the launch of Obie would look like relative to Nurtec? And specifically, do you believe that you could start with the specialists or cardiologists in this case, like you did in the migraine space, before transitioning to the primary care market with Pfizer? Or does a drug like Obie and the fixed-dose combination need to start by launching with primary care physicians from the beginning? Well, regarding the Alzheimer's, you know, tau 217, 181, yeah, we've been told by experts that anything statistically significant from placebo would be meaningful. And so that's kind of what we'll have fairly significant numbers in the trial. Again, not all of them will have elevated levels at baseline. So until we see, you know, the percent of patients with ApoE4 and the number of patients that have elevated tau at baseline, I can't give you a distinct answer yet. But we have a lot of patients. We have, you know, 2,500 patients in the trial overall, so it'll be based on true statistical analyses. You know, what happens between the different biomarkers and placebo. Then I'll let B.J. answer the second question. Sure. So great, great question, Tyler. Thank you. And I'd say, you know, in terms of comparison with what we did with Nurtec ODT and what will happen here with Obie, I think it's a very similar approach, which is, you know, it's really not determined necessarily by distinctly, do you go to specialists or do you engage primary care? It's really around who are the early adopters in each category. And that's how we can actually be extremely targeted, extremely efficient, because you can look back at that secondary data and basically determine who's going to be willing to write a branded in the early stages, not just in CV, but even across other disease states. And you can see that very clearly. Now, our expectation is gonna be highly indexed towards specialists out of the gate, but there are high-prescribing, you know, primary care that have very large, you know, sets of patients in that space that are also early adopting, want to do the right thing for their patients. They, you know, are more innovative in terms of their thinking. We would target those folks as well. But it's a very similar approach to what we did with... I'd say with this very precise kind of, you know, analysis that we do to determine who we need to go to and then what that second sequence is, right? Once people start to sign up. Yep. Can I say something about the Alzheimer's, Michael? Okay. So, Tyler, of all Alzheimer patients, about 65% carry an ApoE4 allele, so it's by far the most important risk factor for Alzheimer's. If you go to an ASCVD population like BROADWAY, about 30% of that population carries an E4 allele, because E4 not only promotes Alzheimer's, it also promotes heart disease. Thirty percent of 2,500 people is about 800 people. ... I mean, two-thirds of those will be on drug, one-third will be on placebo. That's the largest phase II Alzheimer trial ever, because it'll be about 500 people on active drug and 300 on placebo. So anything that is different, as Michael was saying, from placebo, is already very fundamental. So that's all we need to do. So what we do, we do phenotyping for APOE at baseline, so then we can determine who's an APOE4 carrier. Then we do the phosphorylated tau 217, which is now considered by neurologists to be a biomarker for Alzheimer's, and then we simply follow that over the space of a year to see whether the curves are different between placebo and treatment. So that's what we have. Yes, I think, yes. Oh, oh, sorry. Hello. Roanna, okay. Hi, I'm Roanna Ruiz from Leerink Partners. I had a question about the REMBRANDT trial, the new one that you just started. Uh-huh. Could you talk a bit about how that could enhance the FDA's view of Obie's effects? And when the results do read out, could we compare that to any approved agents, on the market? Sure. So we are like, like Wayne Gretzky says, "You go where the puck is going" approach. And there is a lot of. There's already was been FDA interactions with the imaging community on using this as a regulatory endpoint, non-calcified plaque volume. So I know everyone looks at. Right now, a lot of people are doing calcium scanning and seeing plaque, and that's calcified, but there's the non-calcified plaque volume, which is what's modifiable. Over time, it becomes calcified, non-calcified goes down, and there's a number of companies starting up just to do this. One's called Cleerly, HeartFlow, and others as well are developing very, very significant networks of imaging sites to measure plaque. So the FDA, as they have in the past, like with carotid IMT or IVUS, you know, have allowed imaging to be in the label. So I think, over the next few years, there will be a lot of work being done on this endpoint being validated through that, you know, through that process. The FDA does have a whole group that, you know, validates imaging biomarkers. So, as John said, we're not banking on that yet, but we're already noticing that, for example, Amgen is using the HUYGENS study, which is an imaging study in their promotion, and they're... And it's, and according to what I've been told, it's highly effective, that the imaging, and if, whatever... I'm a cardiologist, like others, and cardiologists like to see plaques going away. It's either with a balloon smashing it open or a drug affecting it. It makes a difference. And so, at the very least, we believe that it will be a something we can discuss with physicians in a promotional way, may or may not be in the label. Wait, what Amgen does, just, I know it's getting in the weeds, but they're allowed to talk about the GLAGOV study, but not at the same time talk about the FOURIER trial. Yeah, they can talk about it, but not link it at all to outcomes. But it's one of those kind of rules you have to follow. So we will obviously be paying close attention to that, when we start using the REMBRANDT data, which will, by the way, won't be out until after PREVAIL. But it soon—hopefully soon after PREVAIL, it'll be available, and we can... PREVAIL is our outcome study, and then for the FDC, again, we want to show it's the Entresto of lipids, and I... Nothing could be more effective on getting its own identity than having a plaque-melting therapy showing imagings of that for patients. Even patients themselves, I think, would get excited about that data. So that's gonna be a, you know, part of our commercial story with the fixed-dose combination. Got it. And one follow-up, for B.J. In terms of your payer discussions so far, I know it's early days, but any top questions or themes that are coming through on Obie? Good question. We really. There aren't any themes that you wouldn't imagine. I mean, there's the dialogue and discussion around, well, is it really differentiated from what's currently on the market? It's what's the real unmet need that this will address that others will not address? I mean, that's what I would expect to hear from them. But the good news is, very receptive to the dialogue and discussion. As I mentioned before, you know, now I think payers are in a space of it's not a matter of if they're gonna cover, it's how they're gonna cover, right? In this space, 'cause there's a need, and that's what I think is that really wide opening that we're seeing now in the broader marketplace that will be a part of our reality when we launch. I would just—'cause I listen in on these payer discussions. I find them interesting. They... I would say a large percentage of them were very impressed by the differentiating features, the Lp(a), the diabetes, you know, the small particles. They see it as differentiated, and again, like I said, that's something that we want to continue to develop the science around those elements of obicetrapib. And the payers were receptive to that, and... But it all comes down to, at the end of the day, getting physicians and patients excited about the drug, and that, you know, that enthusiasm for the drug will... Let's put, I don't know the right word, way to say it, put pressure on payers to give more access to the drug. Yes, okay. Yes, Rami Piper Sandler. First of all, great R&D presentation. You unveiled PREVAIL, BROOKLYN, and BROADWAY baseline. You started a fourth study, you gave commercial insights, so really well done. I guess, when you did the nice risk reduction in PREVAIL, using the baseline demographics that you just shared, which component has the greatest contribution, right? And you also didn't show Lp(a), even though it has such profound effect. So are you just waiting for that? I would love to know what that number is now and- Right. Because everything is pointing truly beyond 20%. So that's sort of bucket one question, and then the second question is, just talk about the execution of these, you know, BROOKLYN, BROADWAY, and TANDEM, in terms of what's being done behind the scenes, because obviously, the first data readout really, you know, gets people excited. So, like, how often does-- Just kinda, like, housekeeping stuff. Yeah. Like, who oversees it? What's being done? What are things that others have not done that you guys are doing? So. Right. Right. Appreciate any color. So, I got to call Doug up, actually, our Chief Operating Officer, who is really the- The engine ... the engine behind all this, execution. But I'll answer your first question. So I showed all three, LDL, non-HDL, and ApoB, because experts disagree on what is the best of the three. You go to Oxford, it's all LDL, maybe non-HDL. You talk to others, it's ApoB. The bottom line is we want to show all three. Just to say that if we look at our modeling, no matter how you look at it, for LDL, non-HDL, ApoB lowering, we hit the 20% threshold, effect. We look at LDL part, with small particles, I personally believe it's gonna have a huge impact on outcomes. We don't know. We don't have any evidence of that in the trial yet, 'cause no drug has done this before. Lp(a), Lp(a) lowering, again, we're waiting for HORIZON. I think the challenge there is that you saw this, the skewed curve there. These patients are not enrolled based on Lp(a) elevation, and so only roughly a third have high Lp(a), and so the benefit in that one-third, you know, could be greater. How much that contributes to the overall benefit, is... We don't want to model any excess benefit for Lp(a), but, but the truth of the matter is, we believe it is gonna have a benefit. We, we believe it's gonna have an impact, but we don't wanna, we don't wanna count on that when we think about how the study should be, considered for, for potential outcomes. John, do you want to add? Yeah, I think we're just trying to be very modest, because also, you can also good model in the diabetes also. Because if there's a 16% reduction in diabetes, you can model some of the outcomes there, Lp(a), the same particles. But we've kind of taken a conservative stance and said we have great data on LDL, best data in the world. There's no other specialty in medicine that has data like we have for LDL. Non-HDL, mostly Oxford data, and ApoB, more recent, and there's a paper coming out very, very soon in Lancet, that's going to be online, that's going to talk much more about ApoB. So we have in all three. So there we have so much science that Michael and I can be sure what it means in terms of translation. The rest is just bonus. Right. Uh- Yes. So as far as the trials, the team is working very, very hard to make sure the data is clean. Now, we're lucky. We're working with probably the most experienced LDL-lowering CRO on the planet, and we are right now doing a mix of on-site monitoring at the sites and remote monitoring through the data that we collect. So we can see, you know, how clean the data is. So we are right now focused on cleaning those data and getting all the patients in for their last study visits. We're checking all the labs, especially the LDL, to make sure we have it all. So we are using other samples that may have been stored, that were drawn for something else. We are filling any hole that was left in those studies. So that's happening right now, very intensively for BROOKLYN. It's happening for BROADWAY. For TANDEM, we're working with Ashish at Cleveland Clinic, and we are focused on enrollment right now. So we are focused to get the enrollment done as quickly as possible. We, we are almost there. It's going very, very well, but that is what we're focused on for TANDEM. But for BROOKLYN, for BROADWAY, it's about data cleaning, and then PREVAIL, we're focused on retention, right? Keeping all the patients in. We're watching very, very closely, again, a mix of on-site monitoring and remote data monitoring to see if there are patients at risk of drawing out or falling out. Then we go to the site, we talk to the investigators. So we're working very, very hard to make sure that the data are clean and complete, mostly with our partners like Cleveland Clinic, like our CRO, and Monash in Australia with Steve Nicholls. So yeah, and so B.J. said it well. I mean, this team has had exceptionally good execution, and so now the drug will hopefully, God willing, perform well, and that will turn over to an excellent commercial team that can match the excellence of the operational team to deliver the patient you know drug commercially to patients. That's, that's kind of our vision, you know, for the company. All right. Yeah, we're gonna take one more before the break. So I believe, Debjit, you have a microphone, and then we'll have a second Q&A session after our KOL panel. Okay. Awesome. Hey, good morning. So, Debjit from Guggenheim, a couple of questions from my side. Will you have the CVOT data at the time of approval? And if so, how are you thinking about pricing in case MACE benefit is over 20%? And the second question is more on the two oral PCSK9s, which are in development. How are you guys thinking about, you know, long-term competition from that class? You want to do the- Sure. Pricing? Yeah. Sure. Unless you want to- If you want to handle pricing, that's fine. No, I appreciate the question, and I- ... cannot have any substantive discussion around pricing per se. What I'll just say is the following: there's a lot of work that we have to do between now and what is, you know, our launch date, and the marketplace is actually going to shift as well, you know, during that time frame. So, we're doing our fundamentals right now. We feel very confident. Again, as Michael said, we're hearing directly from payers, is that they see a differentiation here. So, that speaks to what we believe is from appropriate pricing, I'll say. That's as far as I can go right now, but more to come. But I do, I think just again, we want to emphasize the point we made. We have a great drug, a better drug than any other CETP in our class, but I think other than even oral PCSK9s. And we hope, you know, that we have to. The drug has to prove itself, but we designed the drug trial, the PREVAIL trial, to try to be above that 15% threshold that the PCSK9 inhibitors trial showed, and try to be closer to that 20%, driven by longer duration and greater absolute LDL lowering that does drive the relative risk reduction. And so for oral PCSK9s, we are really grateful we're going to have big players in the market with us, because the most important thing is treatment inertia, getting people to goal. And then they're going to be talking about those same things. That takes a lot of the weight off of that messaging that if we have multiple companies doing it, it's even better, supporting education, supporting access to physicians and talking about it. But we believe at the end of the day, it's our profile, it's our, it's our Lp(a) lowering, our diabetes benefit, our small particle reduction, even HDL raising. We're not, we're not trying to say it has any benefit other than we, we know it's very safe to have high HDL. That's just shown that the anacetrapib trial. We've heard people talk about the danger of high HDL, and it's just totally a myth. There's no evidence of that whatsoever. In fact, just the opposite. We see greater mortality reduction, the higher the HDL. So we want to try to obviously correct that misinformation out there. At the end of the day, it's the profile of the drug we believe is going to be superior to the oral PCSK9s, but we really welcome them in the market to help really solve the big problem, which is getting more patients' LDL levels down. Okay. It's time. Yeah, we can talk about that. Yeah... Okay, so, okay, break time, right, Hannah? Yep. We'll take a 5-minute break. Break time. Take a five-minute break. Break. There is some additional food down the hall, bathrooms as well, and then we'll come back at 11. Fantastic, John. Fluid. ... Okay. All right, thanks everyone. We now, we're very pleased to have such a distinguished panel, KOL discussion. We have some questions for them, and I think we'll also have a chance for you to ask questions as well. First, we have, all the way closer to John, we have Jorge Plutzky, who's at Brigham and Women's, Harvard Medical School. Yes, he runs the Lipid Clinic. He's also very translational, great scientist, and one of the few that does both clinical and translational medicine, so we're very happy to have him. Ann Marie Navar from UT Southwestern Medical Center. She's our bulldog for getting patients treated more aggressively. She's been really pushing us hard to get more women in our trials, which we've tried to do, and somewhat successfully. We didn't give you the breakdown of women, but we're doing pretty well compared to other large outcome studies. And then Ashish Sarraju from Cleveland Clinic, new to Cleveland Clinic, Stanford-trained preventive cardiologist. Working with him has been terrific as our academic research organization for the TANDEM trial. As I mentioned, it's going extremely well. That trial execution as we have for all our trials, but TANDEM is doing really well, and we hope to maybe beat our timelines for that coming up. So, we'll start the discussion with all of them, and I think I'll... Let's start with the kind of the unmet need issue. We saw the death rates are going up, LDL levels are not going down. You know, why are we failing patients so badly when it comes to getting their LDLs under control? What are we not doing as well as we should be today regarding lipid management? So I'll start with you, Ann Marie. I know this is something you're passionate about. Yes. Thanks. This, you know, as we talked about a little bit earlier, this could be an hour-long conversation, but I'll try to keep it brief. One of the big challenges was the AHA/ACC guideline shift in 2013, which sort of removed the concept of targets, and generally talked more about just sort of set it and forget it for lipid management, and that's been something that I think we all realize has been a mistake, and we see the tide shifting. There's been a number of expert consensus statements that now refocus on targets. The European guidelines, the Asia-Pacific guidelines are now not only focused on targets but also lowering those targets to less than 55, and I expect that U.S. guidelines are going to get back on track with thinking about a number. But we've been kind of going, having to undo some of the damage from that for a bit, but I think that the tide is shifting and moving in the right direction. The other challenge is in lipids, I think, in 2017, when evolocumab was approved, there weren't other... You know, statins were generic for the most part, and we didn't have to think about using branded drugs for lipid management. And in fact, at that time, there weren't a lot of cardiovascular conditions that we had branded therapies to use. The DOACs were were sort of the first ones that came on the scene in cardiology that had very large numbers of patients that needed a branded drug, and cardiologists and cardiology clinics were not used to prior auths and thinking about copays and copay cards and all that stuff. And so, you know, fast-forward 10 years, we've seen a big improvement, and now we all have systems in place to write for branded drugs, and, you know, with the diabetes classes of agents, everybody's getting, you know, GLP-1s, SGLT2s. You can't now take care of heart disease patients without using drugs that require a prior auth. But there was just a lot of headwinds in the last decade, both sort of getting back on the idea of targets and then realizing that we're not going to get there with single agents alone, and that we have to start using some of these drugs that can be more difficult to prescribe. But I think the systems are sort of in place for this to continue to accelerate. Jorge, you want to? Yeah. It's an issue we've also wrestled with and tried, you know, some novel strategies to overcome, and that does give us some sight lines across this particular issue because we've tried to come up with approaches across the 3 million patients followed and covered by Mass General Brigham as a system. And in that system, where we think our internists and doctors are very good, the amount of undertreatment is just staggering, even when people have unequivocal indications and need for LDL lowering, like bypass, stenting, and other just clear-cut need for lowering. So I think the top line would be the undertreatment has multiple different inputs across the system. Has to do with those inputs involving physicians, patients, other factors like, you know, bad sources of information, social media, internet sorts of things, education. I have patients who come in demanding a statin, and I have other patients that I can't convince to take a statin. Sometimes that correlates with, you know, access to medications and undertreatments and bias of education levels, where people say, "I absolutely want a statin. My internist won't give me one," and then someone else is referred. As one patient said recently, when I said: "Why are you here?" They said, "You're the guy who's going to try and talk me into a statin." And so I think there's many different layers to that. It does come down in many ways to inertia, but they can be overcome. I think there's also an element related to the therapies. For example, we've come up in some of the presentations of a patient who might have prediabetes or is worried about a family history of diabetes and says, "I don't want to go on a statin because I've seen the diabetes data," or has had, you know, side effects and thinks they might have an issue. So I think those all set the foundation for why we need other therapies that are even more effective and that can overcome those and address these many different, you know, components of why people aren't getting more treated enough and more aggressively. That can help address that. We also have, you know, important barriers related to cost and prior authorization, the approval process, and a lot of doctors would give up on that, which is unfortunate. I think those are all combined, but I think that inertia and those barriers are across the the spectrum of these different inputs, whether it's doctors who don't know or patients who have misinformation, cost, bad sources of information. ... Ashish, yeah. Yeah, and I agree with everything there. Just share some institutional data that's very personal to me, too. At the Stanford Health Care system, the tertiary care system, we tried to figure this out. We figured out that patients with atherosclerotic cardiovascular disease were only getting statins about 50% of the time, at least in terms of prescriptions, on par with national data. Then we used deep learning to kind of look at all the notes, and about 50% of the time, and we're talking about statins, not even the more difficult-to-get non-statin medications, it was related to patient hesitancy, statin hesitancy, or side effect profiles or concern about diabetes. So, you know, a need to kind of overcome this sort of initial patient hesitancy with a more acceptable side effect profile, with a comparably simple kind of oral agent, you know, would kind of serve those patients. Again, we're talking about a tertiary healthcare system. But yeah, again, just to back that up, you know, it's these patient hesitancy, side effects, all the misinformation on the internet about statins, compounded with the accessibility issues of now the non-statin therapies, I think, are contributing to kind of the trends we're seeing. John, do you wanna... anything to add, John, on your No, I think in Europe, of course, the situation is highly different. When I listen to B.J. and about pricing and about reimbursement, I always sit with my mouth open for an hour because I don't understand a word of what's happening in America. So our drugs are covered by governments, but for the rest, the patient situation and this very strange anti-feeling against statins is exactly the same, and it's very hard to tackle. I think I like B.J.'s idea of having modern ways of tackling this, and I think people like Peter Attia, for example, who himself says that he's on a statin and ezetimibe and a PCSK9 monoclonal to live longer, that that's kind of approaches will, I think, really help in this marketplace. Yeah, I mean, I think we're we in lipid clinics see a little bit of a skewed view, but I would say a large number of our patients are very statin-resistant. They bring up Lp(a) elevation. They bring up diabetes risk. They want to know what their small particle levels are and particle total Apo B. A lot of it's reflecting, you know, the Peter Attia, you know, the podcast that we hear. Do you hear similar things in your lipid clinics as well? Maybe Ann Marie, do you want to start there and Yeah, the Peter Attia thing has actually been kind of great because he talks about Apo B and statins, and people are coming, asking for more lipid-lowering therapy, which has been fantastic. And so, you know, finally, we have something in the mainstream that's, you know, good for lipid lowering. I just want to briefly mention on the payer thing, because we had, you know, we. The PCSK9 launch was a disaster because of the payer issue, and I think Regeneron, Sanofi Genzyme just did not appreciate the degree to which payers could impair physicians' ability to prescribe drugs. I think you get one chance at a first impression, and they both flopped, and it was. It took years and a 50% price reduction for them to actually recover, and they're still, you know, barely getting to where they could have been. That said, I do think that people have learned a little bit of the lessons there, and clinics have adapted. We just presented data at ACC this year about the initial rejection rates for bempedoic acid, and in fact, found the initial rejection rates were lower for bempedoic acid than PCSK9s, and the percent of patients in the first year of availability who are getting on therapy was much higher for bempedoic acid than PCSK9s. And that was, you know, launched during a pandemic, and we can argue maybe it could have been launched more effectively, but I think it was good to see those rejection rates going down. So prescribers are starting to get a little bit more comfortable with it, and I think navigating it a little bit more effectively. I you know, would chime in with some of our experience of... That I think it makes me a little bit hopeful about the future as new medicines come along and an increasing attention to the idea of implementation science. And, you know, our system is incredibly antiquated. You know, when you see a doctor, if we personalize it, if you see your doctor, and let's just focus on hypercholesterolemia, if there's any barrier issue the patient presents or the doctor's wondering about, your doctor has to know what they should be doing. They have to know when they don't know, so that they refer to someone who does know. And then you have to go through all these hurdles of taking a blood test and, you know, the prior authorization. So to try and get the doctors out of the way as representative of the fact that things are changing and that LDL management with the right drugs can be, you know, reasonably straightforward, our approach is to use an algorithm that doesn't involve the doctor, where we'll use your electronic medical record to find you that you're undertreated, and go ahead and treat you. So, and that's, for cost reasons, doesn't involve a physician. The physician expert wrote the algorithm, but a college-educated person is the navigator who executes it. You start calling people and contacting them and saying, you know, "You had coronary bypass three years ago. Your LDL used to be 50. Why is it 150 now?" "I never renewed my prescription." "Boom, you've got a prescription. Go get it. This is why." And then that becomes increasingly relevant with newer meds of like: You should be on PCSK9 inhibitor. You should have ezetimibe added. You should have these newer tools to accelerate that uptake. It just shows you that when we do that at scale, of course, you know, most recent papers have been in 10,000 patients, that you don't hit any side effects, you don't have any barriers, that you can accelerate implementation of new therapies as they exist, get the doctors out of the way, streamline prior authorization. I think that shows you that there's a lot of hope there for not continue to rely on antiquated systems of let's educate the doctors about how to use a new drug, but you can actually do implementation at scale much more effectively, including using drugs where the internist and often, sometimes the cardiologist doesn't know, when should I be using this advanced heart failure medicine? When should I be using advanced lipid-lowering therapies? You can just do that for them. And so I think it represents under treatment, some of the barriers and some of the ways to overcome that, I think have me optimistic that maybe we can get to better treatment. Okay, let's move on to obicetrapib. Now, you've seen the data. You're all very busy clinically taking care of patients. Based on what you've seen today, what do you—where do you think this drug is going to fit in? I'm assuming, of course, you know, it's on the market, outcome data is in hand. What's your view? I'll start with Ashish. Could you—where do you see this drug? Sure, absolutely. And I think relating to your prior comment, too, about Lp(a), small, dense LDL particles, there's we've certainly seen an increasing number of patients in our preventive cardiology clinic, who are very cognizant of these markers beyond LDL cholesterol, beyond even apolipoprotein B, who fly over for second opinions, even internationally, pay ridiculous out-of-pocket costs to the Cleveland Clinic, which makes a lot of money, I'm sure, out of this. But because of that, I think an oral agent that is able to provide, especially in the fixed-dose combination case, LDL cholesterol reduction comparable to that of high-intensity therapy there and thereabouts, but with favorable effects on all these other markers that seem to be at the forefront of patients' minds, be it through podcasts or the Internet, or patients are becoming more empowered, all good trends. Because of all of that, you know, I think the role of obicetrapib there seems to be very extremely promising. I mean, from at least from our academic research organization standpoint, you know, C5 has been involved with a lot of the old lipid-lowering agents, CETP inhibitors, et cetera. But for the TANDEM trial, I can tell you, you know, from an ARO standpoint, the whole team really is going, you know, all out and trying to get patients enrolled, trying to see this trial through completion in a high-quality manner because there's a tremendous belief that this has a strong role based on the patients that we're seeing. Yeah, I think it's, it's nice to see. I mean, when you, when a study enrolls so rapidly, you know it's because the drug that you're trying to give to patients is very, very well-received, so that, that's a good sign. Ann Marie, what do you, how do you think obicetrapib and then the FDC, how, how would you use it in your clinic? So I, you know, from an oral standpoint, it's gonna be a lot easier to take than the oral PCSK9. That SNAC platform is the same platform that is used by oral semaglutide, and you can see the uptake of that versus injection has been pretty low. You have to take it on an empty stomach, first thing in the morning. It's a big harangue. And I think that's gonna be a challenge for the oral PCSK9. The other oral option is gonna be ezetimibe and bempedoic acid, but that LDL lowering is not as robust as what we see with obicetrapib, and the Lp lowering is pretty impressive. Add that to, there was not a reduction in diabetes and CLEAR Outcomes trial, even though some people thought there might be. In fact, the rates of diabetes were identical. So we had the diabetes there, too. I think there's enough differentiation that this may become a sort of leading oral option for patients. It particularly useful in primary care because it takes some time. Even the Repatha injection pen is easy to show someone how to use, but it takes time to do it, and it's much easier to prescribe a pill. I don't think ultimately, though, that your competition is gonna be any of those drugs. The competition is the 95% of patients who need therapy, who are not on it, and then it's gonna come down to that inertia side. But here I think there's a bit of a rising tide floats all boats. There's a lot more people entering the market. There's a lot more conversation around LDL. I think we're gonna have new guidelines, but by the time PREVAIL reads out, that are gonna be emphasizing LDL targets. And so, you know, there's room for everybody at this table. We just got to get the people at the table who need the lipid lowering. All right. Jorge? Yeah, I think, on one side, on the population side, is the opportunity to have something that's simple, straightforward, oral, easier to access, that's gonna have a bigger impact on LDL lowering, when people need that. On the other side of the spectrum, I'm excited about the prospect of having what I think will be associated additive, concomitant benefits from lowering particle numbers, and, you know, potentially having an effect on Lp and these other parameters, not having to worry about diabetes in somebody who has prediabetes, or that I'm concerned about that, or they're concerned about that. So I think there's broad applications in terms of there being just a tremendous amount of need and how often we're, you know, wrangling with things like a PCSK9 inhibitor and getting that approved, the patient to take it, the renewals are even still complicated. And but on the other side, that there's real signs here that may offer opportunities to navigate through some of the more complex things and to add additional benefit. I think that's, you know, what has me excited about it. Just getting back to the, you know, kind of the initial premise of an oral LDL-lowering drug of 40% mono and say 60% in the combo, simplicity and, you know, no, no injections and no injection training. Think about primary care doctors now. How about, how do you think that'll go with primary care doctors? Do you think part of the inertia is because of the complexity of the other drugs available right now, and would a simple, oral, easy-to-prescribe, hopefully, drug make a difference? Ashish, you want to start with that one, too? Yeah. Yeah, absolutely. I think if we look at ezetimibe, you know, at the Cleveland Clinic enterprise level, my anecdotal experience is that primary care doctors are extremely comfortable using ezetimibe monotherapy, and that's when it kind of, the comfort stops. And, you know, then we're waiting for referrals and delays, and cardiologists who then refer to preventive cardiologists, who then have a six-month wait list, and then it's two years later, and then they have an event. Then they see us. Every cardiac surgery patient sees us, and then we say: "Oh, gosh, your LDL cholesterol was very high two years ago, when you were on combination therapy." So, I mean, getting back to the simple oral agent question, I think, yes, at least at the enterprise level, at our institution, I can say that anecdotally, primary care doctors seem to be very receptive to an ezetimibe-like agent that's simple, has a very, has a very acceptable side effect profile, that is not intimidating in terms of patient counseling, in terms of side effect monitoring, in terms of biomarker monitoring, that isn't complicated in terms of managing its complications. You know, I'm optimistic about an agent that meets those criteria and provides, you know, PCSK9 level LDL cholesterol lowering. Yeah, Ann Marie, and then we'll... Jorge, then I think we'll open up for questions. You know, I have sort of two minds on this. On one hand, I would like to be optimistic that primary care is going to do more around lipid management, and I think there's opportunities for that to happen. If the guidelines simplify and give people targets, it's a lot easier to sort of knee-jerk and add on drugs, just like we do for cholesterol... or for blood pressure lowering or A1c management. We also see primary care doctors prescribing a lot of GLP-1s and a lot of SGLT2 inhibitors, and those are drugs that require prior auth, so they're used to telling, you know, to some of these more complicated drugs and prior auth. So I think there's some reasons why we could expect them to get better. On the other hand, I think fewer than 10% of primary care docs have prescribed a PCSK9 inhibitor to date. So there is a little bit of, "This isn't my job." I think there's a little bit of, that is sort of left to the cardiologists or the specialists, and, that's going to take some effort to get a little bit sort of empower the primary care doctors to prescribe these agents a little bit more. That said, a small delta, a small uptake in the percent of primary care who's thinking about lipids would translate into a massive population benefit. So I think it's worth the effort. There's, you know, so I would hope that that can change. You know, ezetimibe, even with its efficacy, and what is a very good tolerability profile, is really underutilized. I mean, it is really underutilized. If you look at the PCSK9 inhibitor trials, those people who had LDLs of roughly 90 already had events, and, you know, a very low percentage were on ezetimibe. And so one of the possibilities around that may be that it's just not efficacious enough on LDL, and that the idea of having something that could alone do much better than ezetimibe and sort of replace it in terms of use, or could be combined with ezetimibe and have even greater efficacy, I think has appeal. You know, one of the top lines, and we do try and boil these things down for internists and even our cardiology colleagues in trying to move the needle on this, is that the top line out of the PCSK9 inhibitors trials was we can retire that lower is better and that we now know lowest is best. And so the number of times I've back-titrated is very limited, and when I'm worried about someone, I'm looking for more LDL lowering, especially if they've had events. So the prospect of doing that, I think, is appealing, and doing that either, you know, with ezetimibe or just separate from ezetimibe, or having a bigger effect, I think, has some of that potential for an impact on therapy. Being able to reach for something that'll be more definitive and doing that earlier, and upfront, I think is quite appealing. I'll give two vignettes to the extent that they sort of illustrate some of the things we encounter. I was just on inpatient duty, cath lab sent up a patient who had had an MI and had been stented and had already initiated Atorva and ezetimibe, which- Yeah ... is part of the evolution of saying, "Well, we're going to give this patient Atorva, wait for their numbers to come back, and then add ezetimibe." But they were already doing that up front, so that's encouraging to me that people are getting this message. And then the other one is in clinic. When I'm seeing a patient, I'm supposed to talk them into LDL lowering. One of the things that I found interesting, and within the HIPAA restrictions, is that sometimes I'll turn to the resident or fellow who's with me in the room, and I'm having a conversation with someone who wants to debate me about, you know, I'm going to get, you know, muscle issues, I'm going to get dementia, I'm going to get diabetes. And I'll turn to the resident or fellow on call and say, "You know, don't answer this if you don't want to, but are you on a statin?" And more often than not, they say, "Yes." And I say, you know, "Are you 15?" And they go, "No, I'm 28." I said, "Well, why are you on a statin?" And they say: "Because I don't want to go through... My baseline LDL was 120, and I don't need to go through life with an LDL of 120 with a treatment that I think is safe and effective, and I'm willing to take like a vitamin." And then I'll turn to the patient and say: "What do you think this Harvard-educated resident or fellow knows that you don't know, and what do you think you know that they don't know? Usually, there's a long pause there. You know, because—and it is, we've actually taken a look in the Physicians' Health Study, the number of physicians who take a statin without meeting any guideline indication is, you know, quite high. And so I think that reflects, you know, the opportunities there and sort of shifts in perspective that may relate to, you know, a safe, effective, simple therapy that gets you greater LDL lowering. Well, thank you. Yeah. I still think a lot of doctors I see have statin intolerance, though, so we're- Well, that's 'cause they're crazy, too. Right. But, uh- Crazy. but usually, you can, you know, work around that. Well, you know, we, you know, with a really safe and effective drug, I think many of us would use ezetimibe as a placebo control, and if you react to ezetimibe- Yeah ... I'd say, "Well, this is, you know, something for the psychiatrist. I'm not going to be able to solve this." Once I explain to them that ezetimibe is not a statin, and, you know, we all have different things. And I say, "Well, if you told me you had a peanut allergy," and I said, "You know, here's an orange," and you said, "I just told you I have a peanut allergy," you, you'd say, "Well, that guy's crazy," because peanuts and oranges got nothing to do with each other. So if you're reacting to ezetimibe, that's just, you know- Right ... very unlikely to be the case. So I think there's a possibility of doing that with other drugs that are safe, effective, no, no muscle issues- Right ... and circumvent that. Great. So I think fantastic, panel. So, we have a few minutes for questions, right? We do have a few minutes. Great, thanks. Matt Phipps from William Blair. Thank you all for the time today and walking us through the, I guess, the challenges of treating patients currently. You mentioned all the... a lot of talk on the hesitancies of patients and statins. And while maybe a lot of people have questions on the HDL benefit from previous trials, I do think there's a general consensus or, like, you know, thought in the, in the patient world of, like, HDL is better. HDL is the good cholesterol, right? So I guess if obicetrapib works out, and there's a drug that raises HDL, whether or not that's, you know, how much benefits that adding, but then also has this potential reduction in diabetes. Do you think that's enough to, like, pull patients onto therapy that, you know, you were really hesitant as well, if you can show them that profile? If this drug lowers diabetes, it's going to make my job so freaking easy. Because the one thing people are more afraid of than a statin is diabetes. Now, I don't necessarily think that's not like a make or break for this drug, but if that is true, that's like the icing on the cake that will make this amazing. So for that part of your question, if this drug prevents diabetes, it's going to be very easy to prescribe, and I think people are going to come asking for it. But the other point that you made around HDL, it's actually a challenge that we face in clinic, is trying to tell people like, "Yes, your low HDL is bad for you, but we're not going to put you on niacin to raise your HDL." It, people are still sort of fixated on it. I still have people, and yesterday in clinic, I had a patient who said that they were told by their primary care doctor that their ratio was okay, so their LDL of 140 was fine. Which just... You know, I wrote their primary care doctor a letter and was like: Let me tell you what is the case on this. But there is a lot of feeling around HDL, and it's not just that that's going to make people want to get on it, but I think when people see those changes on their lipid panel, we check lipid panels at follow-up to reinforce adherence. People feel good seeing their LDL go down. I think they're going to feel good seeing their good cholesterol go up. And then the other piece of this on the Lp is there's going to be a bunch of frustrated patients whose Lp levels are going to be less than 175 nmol, who won't be eligible for these therapies if they work. But they're going 75 mg/dl range, not high enough to meet eligibility criteria, but high enough to elevate their risk. And we do see already in clinical practice, people using injectable PCSK9s as a... In fact, my preventive cardiology group, when we see people with high Lp(a), that helps us decide, are we going to go bempedoic acid, ezetimibe, are we going to go PCSK9? And if their Lp(a) is high, we preferentially go PCSK9. But I'll mention that PCSK9s, although they do reduce Lp(a), they're actually attenuated. The amount of Lp(a) lowering is attenuated in people with the highest Lp(a) levels. So they're not actually that good of Lp(a)-lowering drugs. The waterfall plot for PCSK9 is not pretty in the highest Lp(a) group that you want to look at. And so, you know, the magnitude of Lp reduction for this drug is higher than what we would get for the monoclonals, and I think that could be a very useful differentiator. And we're going to see testing of Lp be going up and up and up as these companies are entering the market. Then one quick kind of housekeeping question. You all get PCSK9 utilization in BROOKLYN and BROADWAY- Yes ... but not PREVAIL. Can you comment on that? And, and just curious if you can comment at all on GLP-1 utilization in the trials. It's become a big topic post- Yeah. Doc, do you want to... Do you want-- Yeah. There's negligible PCSK9 use in PREVAIL. That's why I didn't give it. We have the most in BROOKLYN, which is, I think, 19%. Yeah, 19% in BROOKLYN. Which makes sense for HeFH. Yeah. There's little use in BROADWAY as well. And, and- Yeah, well- Do you know the GLP-1? GLP-1 use or PCSK9 use in PREVAIL and BROADWAY. So very negligible PCSK9 in PREVAIL. A lot of it is outside the U.S., where it's very, very... You can't get it unless you have FH in Europe, and so this is ASCVD population, and so very little of that in PREVAIL. And then GLP-1s, because we have. It's mostly for diabetes. We have about 19% in BROADWAY, right? ... Although it's worth noting that in the SELECT trial, which I was involved with, the effect on LDL was quite modest, and so I don't think it, it goes to the idea of different mechanisms and input to risk. And that I think we'd still expect to be complementary, not erosive of the benefit you would, you would potentially see. So I'm, I'm not sure that'll be a, a big factor, and of course, there's other, other things going on about the extent of their use, that could be relevant. I do think that if you could also say broadly, you know, related to the questions you asked, that really there's probably no greater triumph, or you could argue the point about is there a greater triumph in biomedical science than what we've seen with cholesterol and cardiovascular outcomes? You'd have to come up with something in the cancer space that could be applicable to so many people. But you might have thought that the story was over with statins, and look how many chapters we've had of things that worked, that continue to work. And so one aspect of that is going to be the tailoring of therapy to a given patient and what their concerns are and what the opportunities are for risk reduction. One of them is just going to be your LDL needs to be, you know, much lower, and we haven't gotten there. Here's a therapy, you could do it, and there are other corners of, like Ann Marie just said, about Lp(a) or other factors that are guiding that. People with persistent elevated particle numbers or non-HDL say, "I need more on top of the statin, ezetimibe." And that's because of the success that we've seen across the board, you can't just say, "Here's a very safe, effective oral treatment that's going to lower LDL," but then there will be other opportunities to say, "Yes, I know you're concerned about you. You have prediabetes. Let's go with this drug that doesn't have an effect on A1c." So I think those are, you know, part of the opportunities that are out there. Michael, can I say one word about- Yes, sure. So what you're saying, Matt, so there was a post-hoc analysis published, I think, last week on the SELECT trial that showed that actually that 20% risk reduction is independent from the percent weight reduction, which I found incredibly amazing. So if you only have a 5% weight loss or a 10% or a 15%, the 20% is 20% across the whole board, which kind of tells you that the mechanism for cardiovascular prevention comes from the GLP-1 itself and has very little to do with the weight loss. But it also tells you, if you look at the LDL-lowering data in SELECT, there's almost no effect on LDL. So that 80% that remains is probably, to a very large extent, lipid-driven. It's not inflammation because CRP was down by 38%, so inflammation is addressed there, but lipids are in fact... Diabetes is addressed, too, of course, because of the insulin, but it's mostly that 80%. So I think the GLPs and their increasing prescriptions are actually gonna help us. They're gonna help all lipid-lowering drugs because people are gonna realize that 20% is great, but there's still 80% remaining that's mainly lipid-driven. At least that's what I consider. Okay, I think we have time for what? We do have some- 1 more, 2 more, 2 more, 2 more quick questions, right. Thanks. It's, Leonid from RBC Capital Markets. I have one question, maybe one really quick follow-up, for the panelists. I'm assuming all of you are now, I guess, supporters of obicetrapib. But I'm curious, when you were first presented with another CETP inhibitor, I guess, what was your initial reaction? And I guess, how long did it take for you to come around, or were you on board right away? I guess I'm just trying to gauge how your colleagues might think about being presented with a CETP. I can start. So, when I first heard about another CETP inhibitor, I'll be honest, you know, I think like all of us, we came into it with a little bit of knowledge about kind of the CETP story. There was torcetrapib, which had off-target effects on blood pressure increase and things like that. Then there was evacetrapib, you know, which had not a very long follow-up time, so it was stopped early, and anacetrapib, which showed positive effects and, you know, actually decreased LDL. So this idea that LDL lowering as the primary mechanism of achieving outcome improvement, as opposed to HDL increase, which had been the initial thought, you know, when I first heard about it, it made total sense to focus on LDL, and then looking at the degree of LDL and the preliminary studies was fairly impressive. And then the more I learned about these, the other effects that we heard about today, the more, you know, again, you know, all, all of us across the row said, "Oh, this is, this is, you know, this is pretty, pretty intriguing." But no, initially, you know, there was, there was this question of, you know, is it, how much is it lowering LDL cholesterol as the main mechanism to achieve outcome benefit, as opposed to focusing on HDL cholesterol, which was the, which was the initial thought process, and then a lack of the initial off-target effect that was seen with torcetrapib, you know, all, all made, made us perfectly accepting of, of this idea to, push through the research, to try to get the outcome data. Yeah, I'll try to be quick. Then, I went to the data to try to understand what's gonna make this drug different, and am I gonna waste my time on PREVAIL for five years, or am I gonna join the team? And the couple of things that moved me, one was the heterogeneity in LDL lowering between different CETP inhibitors, which I think very much explains why dalcetrapib failed. It does not really lower LDL cholesterol. We feel pretty strongly the off-target effects explained why ILLUMINATE and torcetrapib didn't work. But then I was stuck trying to reconcile the last two, evacetrapib and anacetrapib, but there, the follow-up for the ACCELERATE trial was very short. You know, the median follow-up was 22 months. A lot of patients were on drug for a very short period of time, and I tell my patients, lipid-lowering works like compound interest. You gotta start saving, and you gotta watch it accumulate over time. Maybe this room understands what that is. But we didn't give it a chance in ACCELERATE. You know, the trial was just too short, and we have decades of trial experience for lipids to know that you need a prolonged follow-up. So I can reconcile REVEAL and ACCELERATE with the follow-up time and the magnitude of LDL reduction. And then when I saw the amount of LDL reduction, ApoB lowering, Lp lowering for obicetrapib, I'm actually also very reassured now by the upregulation of the LDL receptor. That's a mechanism that we know works by a pathway to lower LDL. The science makes sense to me. In terms of communicating this to the broader audience of people, I'll note that there's probably a decade of people who have come into clinical practice post torcetrapib, who weren't around for that initial part. So I actually think that group's gonna be easier to convince. The people who are sort of still tainted by the torcetrapib experience, I think when you present the differences in LDL lowering, and frankly, the proof is in the pudding. If the outcome trial is a success, that's gonna be pretty sufficient, I think, to move the needle. We're used to drugs that are different within classes. Byetta failed, but GLP-1s are a remarkable success. So we understand the idea that, you know, the same class of drug, you can have one agent that works and another agent that doesn't. And so I think CETP, if PREVAIL shows what we think is gonna show, is gonna sort of align in that same trajectory. I was gonna say the exact same thing and the exact same example of, if you're paying attention, you know that drugs aren't all the same. And you should, you know, we have GLP-1 receptor agonists that don't work, and then others that do. So I think that's not an issue. I think another interesting aspect to the CETP inhibitor field is that you never really had people marketing a CETP inhibitor. So unless, you know, a busy internist out there said: "Well, I, gosh, I really re-read and re-read that New England Journal paper about torcetrapib," they're not, you know. That won't be a barrier. There's not that many that would say: "Gosh, I thought that target wasn't a good one." And I do think the clinical trial data will help, you know, establish that. They're really, you know, very different drugs. It's fascinating. You know, anacetrapib worked, you know, but there are a variety of reasons why that wasn't pursued. It has an incredibly long half-life in adipose tissue that made for a barrier for any company saying, "I don't want to have the conversation with the FDA about a drug with a year half-life. Yeah. Really helpful. I had one really quick follow-up promise, specifically for Ann Marie. I know you mentioned you had a lot of patients with Lp(a), high Lp(a) in your clinic. I guess, what's the overlap between high LDL cholesterol and high Lp(a)? Great question. There's almost no correlation between the two. So, you can look at scatter plots of LDLs and Lp(a) s, and they're very uncorrelated. Lp(a) is almost entirely genetically determined. It depends on what alleles you get from your parents. It's more common in African American or people with African ancestry, but it's very uncorrelated with LDL. There's some correlation with ApoB because an Lp(a) particle has an ApoB molecule on it. But relative to the number of LDL particles you have, the number of Lp(a) particles you have is very small, so even that correlation is pretty small. So the upshot is, if there's a significant amount of Lp(a) lowering, that benefit will likely be independent of the LDL lowering and therefore additive, rather than be sort of cannibalized between the two. Okay, I think, one more. Yeah, last question. Hi, thanks for squeezing me in, George Farmer from Scotiabank. One for the docs and one for the company. It seems to me that the best way to overcome statin side effects is just not prescribe a statin at all. Do you think you feel comfortable administering Obi as a single agent in combination with ezetimibe on the side? That, number one, and number two, for the company, you know, understanding the importance of the REMBRANDT study for marketing purposes, have you thought about employing resources instead to an outcome study with the combo, the fixed combo with ezetimibe instead? Do you wanna... The panel wanna answer the, using, the Obi and, or as a monotherapy? Short answer is I would do it, but we got to. We always start with statins. If somebody's intolerant to statins and they can't. The maximally tolerated statin is zero, then the world is your oyster, and we go to the same conversation we would have if your LDL was 100 on a statin versus if your maximum statin is zero. So we always try to get people on a statin, in part because they're cheap, generic, they have the best outcome data, the most long-term safety data, and I don't think we can throw that baby out with the bathwater. I still feel very strongly we start with statins. Where on the generic spectrum we do start to leapfrog is instead of doing statin, then ezetimibe. If your LDL is sufficiently high on a statin, I will often, and you have the right insurance coverage, I will often add a stronger LDL-lowering drug, either combination bempedoic acid and ezetimibe or PCSK9, rather than statin step-through, because 15%-25% LDL lowering is not that much, and frankly, we haven't mentioned here, but the IMPROVE-IT hazard ratio was 0.92, an 8% reduction at, like, a seven- to eight-year follow-up. I think that's the other reason why ezetimibe hasn't really penetrated that much, is because the hazard ratio just wasn't that strong. People are like, "Eh, it's not that good of a drug." So would I use Obi in combination as monotherapy? Yes. Would I skip trying a statin in the first place? No. Okay, and then regarding REMBRANDT, yes, we'd love to do an outcome study with a fixed-dose combination, but I think the REMBRANDT trial would give us a benefit on the imaging that we obviously, if we're a very successful company, which we hope to be, we could consider an outcome study, but those take years and a lot of dollars. But well, I the bottom line for me as a cardiologist, if we have the imaging benefit, that's gonna be. And if we have obicetrapib monotherapy showing a benefit in PREVAIL, and ezetimibe already having a benefit in its own outcome study, I don't see the need to have that outcome study. But if our synergy is, if we're correct about the synergy and the Entresto concept, we could consider that. But REMBRANDT becomes our proof of concept to see whether we move forward into a big outcome study with the FDC. That's been talked about, even Big Pharma interested in the FDC for an outcome study, but right now we're focusing on our present plans. ... Okay. Can chime in on the statin intolerance question. You know, in our clinic, when we look at it, we can overcome statin intolerance in about 50% of patients. It takes time. It can be time-intensive. And one of the things that's come up recently with the advent of new therapies, depending on someone's degree of risk, is now with alternatives, do we really bother to go through this thing of trying to get someone to tolerate a different statin, and once they know the benefits and know the data, that maybe they'll do better, as opposed to just moving on, because there's other alternatives? We prefer not to, because as Ann Marie said, just the benefits are there and the cost is easy. So I think that this is an example of maybe moving on, and I will say that one little interesting corner of the world is that in a patient who thinks they couldn't tolerate a statin and is fine on ezetimibe, or doesn't have the right LDL, it becomes very streamlined to swap out their ezetimibe for the combination. Yeah. So now it's like, you're not taking any more pills, and you're getting one pill for free because I just switched you from Nexletol, from ezetimibe to the combination of bempedoic acid and ezetimibe. And being able to do that with something that would be even more effective, I think is appealing. And I will say that even though I was involved with the CLEAR Outcomes trial, you know, whether or not that whole mechanism is really true, that you're not getting drug to muscle because it's only activated in the liver, is really, you know, not clear. So being able to circumvent that completely may also have another, another little corner of the world where it's appealing, but to swap out the same number of total drugs for the patient without, you know, an impact on cost, it can be a very effective way to go. Okay. Thank you very much. Very, very, very great panel, and we'll wrap up here in a few minutes. Well, thank you, thank you all very much for coming. Those watching on the Zoom link, too, we very much appreciate all our analysts and support from investors and hopefully new investors that are listening in on today's program. Just gonna make a couple of concluding remarks, and then we can, you know, break, and we'll be around to answer questions as well afterwards. So we're operating from a position of strength. You know, again, the theme of the company is, you know, excellence in science, excellence in execution, in trial design, experience. Also, we're very, very grateful to have a very strong cash position. We did a financing in February to raise $190 million. It was well oversubscribed, and so now we, you know, have $481 million in the bank, and that gives us plenty of cash to take us all the way through the end of the phase, all the phase III trials and give B.J. some support he needs to get ready for the launch. So we're, we're very, very pleased with our, the strength of our cash position, and that makes a big difference as we look forward to where we go over the next two or three years. So in closing, I just want to emphasize the important points about NewAmsterdam and why, you know, we believe we're delivering value for the field, the patients out there with heart disease that need another solution or those who want to prevent heart disease, as well as our shareholders. We're data-driven clinical development. We have a lot of experience on how to conduct trials, and I think you've seen that today, that we've delivered on high-quality execution of trials that are very well designed. The phase II data highlights the value of this drug beyond LDL lowering, and we are trying to address this very unmet need with a potent, well-tolerated, low-dose oral therapy. We have great experience on the team. I want to also mention that Juliette Audet was on our board. Now she's moved over to Chief Business Officer, very instrumental in the formation of the company, and she'll be leading our efforts in business development. We have 12 MSLs in the field, and a great commercial team, and we're seeing much more KOL support throughout the world. CMC has been a fantastic, stress-free so far, development. We've had to overcome some challenges with the FDC that we've now fully accomplished, a great little pill as well, with no effects on... It meets all the criteria that we need for the FDC to move forward into phase III. That you heard from B.J. for the first time, the commercial excellence that we're building as a company and a strong balance sheet that we have to move forward throughout the next couple of years at least. And so, our takeaways, we have a lot of tailwinds behind us. We're gonna have from BROOKLYN the LDL, Lp(a), ApoB, blood pressure, vitals completed and published in the next 12 months. Same for BROADWAY, PREVAIL, full baseline data with a design paper, and then TANDEM will have the results in the next 12 months as well. And again, we're very excited about trying to confirming that, you know, close to 60% LDL lowering, that would make it the most effective LDL-lowering drug, bar none, in a single pill. And we also the headwinds that we're excited about are the label expansions by the FDA. This is a kind of a, an unknown, but we're not exactly sure the motivation. Otherwise, what we've heard from the FDA directly has been they want to make labeling not an impediment for, for payers, I mean, for payers not to reimburse. And so they're seeing, we're seeing broader labels given for primary hyperlipidemia. The goals are already being adjusted with expert panels, and Europe guidelines are set, and that's filtering into the United States. We have more and more expert opinions of hoping for LDLs below 55 for high-risk patients. LP is gaining momentum as a target. It's a drug that obicetrapib can be a big part of that treatment algorithm without even being in the label, because I think it, it'll... Labeling will be limited to those very high levels of Lp(a). And then, the accelerated adoption of the branded drugs and non-statins, and we're very encouraged by what we're seeing in the marketplace. So it's not just our own execution and performance, but we do see a lot of improving elements in the marketplace that puts us in a great position to be ready for launch in early 2027. So I want to thank you all very much again for attending. We, as we always say, we're on time. We, with our trials, we're on time with ending the R&D day as well. So thank you for attending, and we'll hang around for questions. We really appreciate it. Take care. Bye-bye.