NewAmsterdam Pharma Company N.V. (NAMS) Earnings Call Transcript & Summary

Welcome, everyone. 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 on -- in January of 2023, we promised as a company, a small company that we would work as fast and diligently as we could to bring obicetrapib to patients. And I want to really be very complementary 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 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 Topline Japan data Phase II results were also presented and published, and we completed BROADWAY for a large -- much larger Phase III lipid trial. And we released our initial Alzheimer's data, which I'll share more details with you later. And we had our very effective development of our fixed-dose combination and moving forward with the TANDEM trial, which is underway and rolling 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. And 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. This will of course start with our Chief Science Officer, Founder -- Co-Founder with me, John Kastelein; Doug Kling, who has been with me for all my previous companies, he runs the exceptionally fantastic clinical operations group, he is in the audience; BJ Jones, you'll hear more about 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 in public companies, he is here with us today as well. And I also want to not leave out Sheng Cui, who is 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 I hope many of you can 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 -- I actually still see patients at University of Chicago. I run the Lipid Clinic. I see patients 4 days a month, and I still love seeing patients, and that's why I keep doing it. And according to my commercial colleagues, I'm in the top decile of writing lipid drugs. So I'm a very, very busy practitioner. And 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 who understand -- underserved by current therapies. And I see this every clinic, man. We have many patients who cannot achieve the adequate LDL goals for multiple reasons, not enough other options to consider, tolerability issues, other factors that we don't have the right drugs for yet, and we know that heart disease is still the leading killer by far, and it's getting worse. So 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. So here's the agenda. I'm going to start off by giving a clinical update, then I'm going to turn over the floor to John Kastelein to give us a science update. This is -- we're a science-driven company. John and I are both academic clinicians and science is what drives us. And I think you're going to be very excited about all the science that we've been able to develop around this molecule in this field that goes well beyond just the LDL effects of obicetrapib, and we want to share that with you today. For the first time, we're going to have BJ get up and talk about the commercial update. He's had basically 6 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 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, from Cleveland Clinic. These are tremendous thought leaders, and we look forward to their comments. We're going to have some specific questions to ask them. And you'll have a chance to ask questions as well. And we will have some closing remarks about tying this all together and where we're going in the future. So I mentioned this already, but we noticed the data has been not going well for heart disease. And there's many factors to consider, but one of the things that we feel is a major factor is the guidelines removed in 2013 -- goals were removed from the guidelines of 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 '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 your statins are the mainstay. They reduce risk, lower LDL. I believe, personally, I've been -- 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 these are fantastic drugs, and they made a big difference in preventing heart disease. However, there is still what we call residual risk. That is the risk that continues despite adequate statin therapy. And the new evidence I described is just one small part of that new evidence, continues to show the part of that residual risk is getting the LDL levels down lower, maximizing LDL reduction to achieve greater relative risk reduction, and 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, residual thrombotic risk. And then I want to talk a little bit about, and John will go into more detail about, where obicetrapib is differentiated from any other LDL-lowering drug by its impact on these other parameters. So my previous company, Corvidia, interleukin-6 antibody was acquired by Novo, and that's well underway to Phase III trials for inflammation in heart disease. We have other options that we're also exploring in that field. But when it comes to the residual ApoB, 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 of 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 more particles, and that results in greater cardiovascular risk. And obicetrapib will show you the data, it has a 90% reduction in the amount of small particles, which is the residual -- majority of the residual particles when someone is on a statin. Of course, Lp(a) has become a very exciting target. 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 going to show a benefit of Lp(a) lowering on reducing cardiovascular events. And that benefit, we believe, with obicetrapib can be part of the treatment algorithm. We're not going to be seeking indication for this. But as we share with you later, we have a very prominent effects of lowering Lp(a) that could be an option to consider for patients that do not have the super high levels of Lp(a), above the 90th percentile, where the trials are being focused, but those that have elevated Lp(a) where there could potentially be benefits for 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, the 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 going to talk later, especially with our KOLs about 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 because 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 will still have issues that are problematic regarding the food effect, very prominent, but one point we want to 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 drugs. 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 options available today. So 30-plus million Americans need more LDL lowering despite the standard of care in our monotherapy based on our pooled Phase II data lowers LDL by 43%. Then with our fixed-dose combination, we're going to 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 going to 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 our -- all our Phase III trials. We're blinded to safety, 2:1 randomization in both Brooklyn and BROADWAY, 1:1 randomization in PREVAIL -- we have 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 want to not just have a better drug, but a better clinical trial program to develop this drug. And we've been very fortunate to learn from the past about what was done right, what could have been done better 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, greater absolute reduction in LDL to support a greater MACE benefit. And then duration, 2.5-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 a Repatha trial. It's only 2.3 years duration. If patients, who are on the drug for just a year, the relative risk reduction went from 15% to 20%. So a big difference just by having a 1-year minimum follow-up, and we have a 2-year minimum follow-up -- 2.5-year minimum follow-up for our patients. And then the other benefits that I alluded to, we will go into more detail later, demonstrates a differentiated profile that's going to 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. We are 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 are 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 to, 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 moved 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. And 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, it should translate to a 44-milligram per deciliter 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-milligram per deciliter drop. And then for ApoB kind of the -- 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 no matter how you look at it, LDL, non-HDL or ApoB, we should achieve over 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 at starting that we'll require a tremendous amount of capital, effort to start both a very large outcome study and 2 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, again, BROADWAY and BROOKLYN have finished and start reading out -- BROOKLYN, 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 we'll 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. The FDA wanted high-intensity stands -- use high-intensity stands 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 after the patient is on -- with familial hypercholesterolemia, the BROOKLYN trial, 51% on ezetimibe, which we think is a good thing. We'll show you data again that ezetimibe seems to enhance the effects of obicetrapib. 16% on PCSK9 inhibitors. We know from genetic data there is -- they 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 bit 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 milligrams per deciliter; ApoB, 92, against standard of care, 65% of high-intensity statins; 26% on ezetimibe; some on PCSK9 inhibitors. And while we've been very pleased with both trials, there 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 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 for the first time with any therapy, reductions in what's called hydroxycholesterol in the CSF. The plasma, we see that with statins. But in the CSF, stats have no impact on the hydroxysterols 24 and 27, which were 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 E3/4 or 4/4, and we saw these results across the board. These are all highly statistically significant reductions in these hydroxysterols. 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 myocardial impairment, you'd expect to see these biomarkers of tau and amyloid increasing significantly in 6 months. They were basically flat. In one biomarker, which lecanemab used as its primary efficacy parameter, the A-beta 40:42 ratio went up in the plasma, which is what's your positive sign, went up in 6 months, which was also significant. So we are encouraged by these reductions in hydroxycholesterol and the biomarker changes. So 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 we can use ptau levels, 217, 181, to diagnose pre-Alzheimer's, MCI, and we can look at changes over a year compared to placebo with those plasma biomarkers and that may give us a confirmation of this pilot data as well as then set the stage for further clinical trials to evaluate this end point. As part of our background science, we've commissioned and received many, many supportive data on genomics, loss of function CETP associated with lower risk of Alzheimer's disease, Lewy body dementia, Parkinson's dementia and 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, that 1/3 of 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 we -- 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 again, we've designed it to maximize success. We don't want the trial to fail the drug. The drug may not work, which is always the case with any novel therapy, but we want to 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. The study was started with our partner at the Cleveland Clinic. They have done an exceptionally great job. Enrollment is going rapidly, and we are potentially ahead of schedule on this trial with readout expected in the first quarter of 2025. So this is the -- an LDL trial that will be allowing us to file the monotherapy and the fixed dose combination at the same time, and 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, 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 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, and 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. And 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 be doing short to all of our teams. So I'm not going to read this, but -- and I'll go a little faster. So first of all, I would like to share the Lp(a) results. Lipoprotein(a) 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(a) lowering molecule of Eli Lilly. Everybody has either an RNA-based therapy or an oral molecule to lower Lp(a). And why would that be a good idea? Well, that's because of the middle graph. As you can see, the relation between Lp(a) and risk is completely linear. And there's a very clear hazard ratio of 1 around 30 milligrams per deciliter. I'm sorry, it's not in animals yet. I'm still used to the European way of thinking in milligram per deciliter. So anything above 30 mg per deciliter for lipoprotein(a) is associated with an increased risk for heart attacks, strokes, aortic stenosis, and it's a terrible risk factor. So if you look at the numbers of people that have this abnormality, they are beyond anything that you and I have ever seen. The estimated prevalence in the U.S. is something like 320 million. And globally, it's about [ 700 million ], 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(a). There's no doubt about it. But the distribution in the population of lipoprotein(a) levels is very abnormal because it's not Goshen, it's not normally distributed. What you see here in blue is the majority of the population have a completely normal or either basically 0 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 going to 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. And 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 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 are at 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 had early heart attack, then I think treatment. But 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 the scientist can do is to show a waterfall plot. There's -- because waterfall plots are every bar is a single patient, 0 is the baseline. So there's no lying. This is not like let's look at placebo and then subtract another 10% and 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 2 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 is you can see immediately that some people, and we have 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 2 trials is 57.2% -- 57.1%. 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 put on the slide here, these are the PCSK9 monoclonal antibodies, previous CETPi's, nicotinic acid, inclisiran, ezetimibe, tiny increase or no effect. Some trials show tiny increase, other trials show no effect. So it's very hard to say whether it's exactly 0. And statins add a few percent to Lp(a), probably because of competition for the LDL receptor. But obi, 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 2 things, you look at the synthetic rate, SR, or the fractional catabolic rate, FCR, meaning that if SR is down, 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, Lp(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(a) that drives the benefit? Do you need to get to a certain goal in order to get the benefit? Or is it a percentile difference? And what is the minimum amount of Lp(a) you need to lower and all? 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(a) 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 will 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(a), 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 ApoE3-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 give the mouse cholesterol and a western diet, and at the end, you kill him. And then you basically look at every tissue. 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 ezetimibe and blue is obicetrapib plus ezetimibe. The left panel is CETP activity. After 4 weeks, there is no CETP activity left in the obicetrapib arm, neither at 8 weeks. And this was done to mimic the human situation. Our drug at 10 milligrams inhibits CETP activity by 97%. You cannot discern 100 -- 97% in a mouse, of course, but it basically wipes out CETP activity. Then, 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. So 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 is already there at 4 weeks and then 6 and then 8. 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. So this was exactly what we wanted to happen. And 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 obi on itself already increases this very statistically significantly so. Ezetimibe does it, but 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 this proves it. And 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, increasing 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 matter analysis because their mechanism is very differently. Well, that is nonsense. The mechanism, in fact, is exactly the same. I already highlighted shortly the obi plus ezetimibe combination. Now, bear with me, so in the mice, this is ezetimibe alone, obi alone and this is obi plus ezetimibe. This difference is 49%, and obi mono is 28%. This is ROSE2. This is obi 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% to 18% additional LDL lowering. So we are convinced that there is a synergistic effect, and I've heard it called the Entresto of lipids, 1 plus 1 is more than 2. It's, in fact, 3. And 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 obi 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 the biological basis for this interaction. And here, I'll show to you again, here we are, cross-trial comparisons. So if you go from ezetimibe, baseline simva -- sorry, ezetimibe and 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 obi 10 and then to 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 1, Type 2, Type 3, Type 4 and Type 5, severe plaque. So in these mice, they can very diligently determine how severe the plaques are. And then basically, you give them 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 obi alone, very low non-HDL, and this is the combination. So this is obi alone, ezetimibe alone, and the combination exactly as you see in humans. And also the percentile 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 route and the coronaries and the valves in these mice. And what you can see is that obi 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 4 to 5. 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 wanted to work on advanced lesions because those are the ones that are going to 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 obi and ezetimibe that knocks athero out in general, but then mostly actually on the severe lesion here. Look at that little cross. It doesn't mean that all the mice are dead because everybody is dead here. But it means that this is a statistically significant difference with regards to this and that. So again, the synergy we observed for the lipids. We also observed 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 going to outperform IVUS, coronary angiography, and it's noninvasive. 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 a 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 have 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 drug 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. And also, this trial is designed to demonstrate the clinical benefit of the FDC because we don't have a phase -- 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, 3 weeks ago, the Lancet, read that paper, published a manuscript that showed that high-intensity statin resulted in a 36% increased risk of new-onset diabetes. This number was much higher than previously understood. We always -- Michael and I used to think it's 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 the statins, if that drug could help in preventing that side effect, it 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 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 going to bore you with, is that increasing ApoE on an HDL actually is antidiabetic in many ways; at the muscle, 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 at 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 Obi alone. This is Obi 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 CTP 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 ROSE2, brown monotherapy Obi, 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 ] patient is small particles. And LDL size is small, 20.3, should be above 20.5. If you then give Obi 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. And this profile is especially present in people with insulin resistance, type 2 diabetes, obesity, if there -- and even more so, if they're on a statin. So it's intuitive to be appreciative of the drug that is able to get rid of the small particles and the residual risk associated with that. Then I have 3 slides that I received 2 days ago. So this is totally unpublished data. So there is a whole lot of mediocre signs 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 2 large studies that have done that. And so what -- 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 U.K. Biobank and has done that cubic spline analysis for HDL cholesterol, and look at -- with me at these data. This is all-cause mortality, the most severe readout of anything that we have to offer in clinical medicine. And then you go down 40 to 45, 50 to 70, 75, 95 to 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 0.5 million, 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 nonfatal events, infection, cancers, anything, and he actually looked whether the HDL increase of 104% was related to any outcome in the MedDRA. Well, it doesn't take a rocket scientist to appreciate that there's no risk. So not only is an 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? Oh, BJ, I'm sorry. I forgot. Yes, everyone is waiting for this. We have BJ now coming up to his debut, talk about the commercial story. BJ?

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. So it's great to meet you all. I'm BJ 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 Obi and essentially what our plans are. So as a brief introduction, frankly, I've been in this space, kind of in our industry, working for 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 be -- have a major leadership role in some significant launches on -- these on the left here, it's not all inclusive, but there's 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 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 mammoth market opportunity? But I remember sitting in front of many of you and others at Biohaven having a dialogue and conversation, which many would say and larger competitors would definitely say is that, well, that's good data. And that's really good, but there's no way that Biohaven can do what's necessary to launch this drug. 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 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 do I want to actually get involved in? And there are 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 would bring some type of incremental benefit, but something that was transformational. I also wanted to be involved in the organization, frankly, had the funding to do as 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 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. Obi is different, and it will make -- if approved, will make a profound impact on patients, and that is why, frankly, we're all in the business of what it is that we do. And we have a variable ambition. We expect to transform treatment in this space. Clearly, it's necessary. You heard Michael talked 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 the team, their 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 talk about that. So first, maybe we talk just about the opportunity generally. And I'll say the LLT 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, I'd just say generally, 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, they're actually not at goal. So I would say the sweet spot in some sense, basically says over 40 million patients are undertreated or not treated. That's the space 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. And if we look at the next 3 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 over greater than 4% growth over the last 2 years or so. And if you strip out for 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 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 a 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, memorialized to just show the commercialization specifically in CV therapies broadly, have had the lowest proportion of launches that met or exceeded expectations. And there are some hindrances, right, some challenges in this space versus some of the other areas and also setting very, very high expectations, could be a balance 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 4 primary areas. And it's outlined here, and you can see it kind of in 2 categories, one of which is product specific related, and the other is more around basically an execution element around what happens in launch excellence. And so we'll spend a little time in each of these areas, but the first of which is just poor product differentiation, where new products are actually coming to market, but there are gaps, right? And 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 would call lower prioritization or under investment. But I can tell you with confidence is that NewAmsterdam and Obi 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 because I think that's an important asterisk. And I won't -- you've just heard for the last hour of why Obi is so differentiated. Why do we believe this is really a different maker in the marketplace overall. But I can say that, look, Obi and the FDC basically check all the marks, right, that are necessary. And 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. And 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 the relative belief in just how much of the market that Obi will demand if approved. And again, we've talked about all the special sauce in some senses off on the right-hand side for Obi specifically. But the key piece is if approved, Obi 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 the PCSK9s. It's been many years now. They'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 increase and broaden what is that prescribing base. And it's a real opportunity for us differentially there. Its 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 going to work into our favor. And then Obi 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, and 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 because if you just look at the data here, it suggests that the vast more 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. So the vast majority of them are actually sitting in primary care offices. And so we cannot 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 upfront, 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 we 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 tougher than to kind of dig themselves out of that as well, even after they drop 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 more traction in the space and doing even better. And we believe that our anticipated value proposition, again, differentiate our proposition, expects to accelerate demand and payer access. And when we drive that demand, when we drive that top line, it will impact payers' willingness and ability to, frankly, put us on [ front line ]. And then lastly, in this space, I'd say, look, PCSK9s were differentiated. They brought kind of a new type of efficacy in the space for sure. But the route administration was a challenge for them, right, in limited 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, 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 promotional engagement, they'll be high in the omnichannel 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 has 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 clinic. So there was even financial incentives of clinicians to stay with what was the older medication. I think this is not the only example, of course, but is 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 and Xarelto and Eliquis, has been nothing but what has been a very strong 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, Coumadin declines and declines dramatically. There's also another case that 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. And indeed, this is more recent, but the branded medications were able to penetrate 25% of that generic market within the first 5 years or so. In that example is migraine. And obviously, I'm very familiar with this, just walked away from watching all of this take place being a part of it, understanding what was a key trigger and why it is we were able to grow so quickly in that space. But 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. So yes, 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 #3, is 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, is 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 this has not been able to do. This is the type of tipping point, I think that we're walking into with Obi. 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 a 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, much easier to take place and the dynamic and the one that we're asking for this change, right, is even simpler than those other examples we showed. So then what? So what BJ, 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 3 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. I 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. And 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 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 Obi, 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 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 the 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, I think we're poised for success for all the reasons we discussed, like certainly clinical excellence. I would suggest to you all that it is a benefit to be a smaller organization proven at Biohaven to be a small 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, just top-notch talent that -- you won't find better talent in the industry. And not only was I able to bring over 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 here before. And I think we're off to a very strong start. 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 Obi 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 disease 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 -- with one of you earlier just about we have all this great data that's going to start coming out in '24. 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 value, we believe that, but we don't want it to land with a foot. So we want to 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 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 work for us. We're going to continue to elevate the corporate profile, and our public relations plan is very broad and comprehensive. Hopefully, you all are witnessing this as well. And 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. And 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 PIE deck, okay? So lastly, and I'll close on this, and I believe we're going to have a bit of a Q&A. But if you have heard nothing else or remember nothing else, please remember this, guys, is, we are setting the stage for what we believe is a transformational launch with obicetrapib, is a differentiated product for all the reasons you heard of before is going to deliver 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 those things are shifting in our direction. They are 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 going to invest to win. And what that does not mean is, we do not need to invest in spin like big pharma, 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. And I think we set the model for that at Biohaven, and we're going to pull through what were those learnings of best practice. And frankly, a lot of mistakes that were made as well. We've learned from those as well. So we are -- as you might imagine and anticipate, I'm very bullish about the future and what the opportunity is for us. So I appreciate your time today. Thanks, everybody. And Michael?

So yes, 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.

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 don't expect to see much of a diminution of effect. I mean we looked at all the other, like 52-week trials, like with 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 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 -- you never know till you get the data, but what we can say is we had very, very little dropouts and very little drop-ins throughout the entire trial. And so we feel that there will be -- we're expecting very little impact between week 12, the primary end point 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 -- my point I just want to make about the -- we have a press release, we'll have the day at a press release. We are working with very well-established prominent academic institutions, which have committed us to be pretty minimalist what we can say to avoid any effect on publication. So we have restrictions on that. We don't want to anyway 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 in, this team, we do -- we work very quickly. We're going to 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 on what we can say other than the primary endpoint 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 realized in FH, which was a year, exactly like BROOKLYN. There's [ DEFINE ], which was even an 18-month trial. And REVEAL, we had 4 years -- sorry, yes, REVEAL 4 years and 6.5 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 an outcome trial, there's always an increase 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 BJ on commercial. Like, if you fast forward a couple of years and you have Obi approved as well as the fixed-dose combo. Is there any sort of prioritization between those 2 compounds and how do IP and the IRA impact that decision?

Good question, Dennis. I'd say just generally, that the relative priority, I would say, is balanced and 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 specialists might index more heavily towards the FDC, primary care, more indexed towards the mono. But our expectation is it's probably going to be about 50-50, I think, generally, in our cost. 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 going forward and IRA and all of that is the benefit is, is that we break up essentially what is that overall revenue between the 2, which is the benefit 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. 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 and Ptau 181 or 217 levels? Do you need to gain confidence to move forward and potentially start Phase III that you want, Michael? And the second one is another one for BJ as well. Can you compare in contrast what the launch of Obi 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 Obi and the fixes combination need to start by launching with primary care physicians from the beginning?

Well, the -- regarding the Alzheimer's Ptau 217 and 181, we've been told by experts that anything 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 of baseline. So we -- until we see the percent of patients with ApoE4 and the number of patients that have elevated Ptau at baseline, I can't give you a distinct answer yet, but we have a lot of patients. We have 2,500 patients in the trial overall. So it will be based on true statistical analyses, what happens between the different biomarkers and placebo. And I'll let BJ answer the second question.

So great question, Tyler. And I'd say, in terms of comparison with what we did with Nurtec ODT and what will happen here with Obi, I think it's a very similar approach, which is it's really not determined necessarily by distinctly do you go to a specialist 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 second 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 going to be highly indexed towards specialists out of the gate, but they are high prescribing primary care that have very large sets of patients in that space that are also early adopting one, do the right thing for their patients. They 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, whether it's a very precise kind of 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.

Yes. Can I say something about the Alzheimer, Michael? So Tyler, of all Alzheimer's patients, about 65% carry an ApoE4 allele. So it's by far the most important risk factor for Alzheimer. If you go to an ASCVD population, like BROADWAY, about 30% of that population carries an E4 allele because E4 not only promotes Alzheimer, it also promotes heart disease. So 30% of 2,500 people is about 800 people. I mean 2/3 of those will be on drug, 1/3 will be on placebo. That's the largest Phase II Alzheimer trial ever because it will 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 is an ApoE4 carrier. Then we do the phosphorylated tau 217, which is now considered by neurologists to be biomarker for Alzheimer. 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 -- sorry. Roanna, okay.

I'm Roanna Ruiz, from Leerink Partners. I had a question about the REMBRANDT trial, the new one that you just started. Could you talk a bit about that could enhance the FDA's view of Obi'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 Wayne Gretzky says, you go to where the puck is going, approach. And there is a lot of -- there already has been FDA interactions with the imaging community on using this as a regulatory end point, non-calcified plaque volume. So 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, noncalcified goes down. And there's a number of companies starting up just to do this. One is called Cleerly, HeartFlow and others as well are developing very significant networks of imaging sites to measure plaque. So the FDA, as they have in the past, like with Carotid IMT or IVUS, have allowed imaging to be in the label. And so I think over the next few years, there will be a lot of work being done on this endpoint being validated through that process. The FDA does have a whole group that validates imaging biomarkers. So as John said, we're not banking on that yet, but we are already noticing that, for example, Amgen is using the [ HAUSER ] study, which is an imaging study in their promotion. And according to what I've been told is highly effective, the imaging -- I'm a cardiologist, like other cardiologists like to see plaques going away. It's either with a balloon smashing it open or drug affecting it, it makes a difference. And so at the very least, we believe that it will be something we can discuss with physicians in a promotional way, may or may not be in the label. What Amgen does -- I know it's getting into the weeds, but they're allowed to talk about the [ HAUSER ] study, but not at the same time, talk about the FOURIER trial. Yes, 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 by the way, won't be out until after PREVAIL. But hopefully soon after PREVAIL, it will be available, and we can have PREVAIL as our outcome study. And then for the FDC, again, we want to show us the ENTRESTO of lipids. And nothing could be more effective on getting its own identity than having a plaque melting therapy showing imaging of that for patients. Even patients themselves, I think, would get excited about that data. So that's going to be part of our commercial story with the fixed-dose combination.

Got it. And one follow-up for BJ. 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 Obi?

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 in 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 discussion. As I mentioned before, now I think payers are in space. It's not a matter of if they're going to cover, it's how they're going to cover, right, in this space because 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 -- because I listed in these payer discussions. I find them -- it's interesting. They -- I would say a large percentage of them were very impressed by the differentiating features, the [ LP(a) ], the diabetes, the small particles. They see it as differentiated. And 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 enthusiasm for the drug will -- let's put that on the right way to say it, put pressure on payers to get more access to the drug.

Yas Rahimi, Piper Sandler. First of all, great R&D presentation. You unveiled PREVAIL, BROOKLYN and BROADWAY baseline. You started a fourth study. You gave commercial insight. 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 a profound effect. So are you just waiting for that? I would love to know what that number is now. And 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 BROOKLYN, BROADWAY and TANDEM in terms of what's being done behind the scenes because obviously, the first data readout really gets people excited to like how often that's just kind of like housekeeping can stop like, who oversees it, what's being done, what are things that others never done that you guys are doing. So appreciate any color.

Right, right. So I got to call Doug up actually, Chief Operating Officer, who -- he's really the engine behind all this execution. But I'll answer your first question. So I showed all 3 LDL, non-HDL and ApoB because experts disagree on what is the best of the 3. You go to [ Oxford ], it's all LDL, maybe non-HDL. You talk to others, it's ApoB. But the bottom line is we want to show all 3. Just to say that if you look at our modeling, no matter how you look at it, for LDL, non-HDL, ApoB lowering, we hit the 20% threshold effect. When you look at LDL small particles, I personally believe it's going to have a huge impact on outcomes. We don't have any evidence of that in the trial yet because no drug has done this before. [ LP(a) ] lowering, again, we're waiting for HORIZON. I think the challenge there is that you saw the skewed curve there. These patients are not enrolled based on LP(a) elevation. And so only roughly 1/3 have high LP(a). And so the benefit in that 1/3 could be greater. How much that contributes to the overall benefit? We don't want to model any excess benefit for LP(a). But the truth of the matter is, we believe it is going to have a benefit. We believe it's going to have an impact, but we don't want to count on that when we think about how the study should be considered for potential outcomes. John, do you want to add?

Yes. I think we're just trying to be very modest because also -- you can also could model in the diabetes also because if there is 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 is 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 3. 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.

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 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 visit. 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 feeling any hole that was left in those studies. So that's happening right now very intensively for BROOKLYN. It's happening for a 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 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. And then we go to the site, we talk to the investigator. 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 Stephen Nicholls.

So BJ 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 it can match the excellence of the operational team to deliver the patient -- drug commercially to patients. That's kind of our vision for the company.

We're going to take one more before the break. I believe, Debjit, you have a microphone, and then we'll have a second Q&A session after our KOL panel.

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 2 oral PCSK9s, which are in development. How are you guys thinking about long-term competition from that class?

Do you want to do the pricing, yes?

You want to handle pricing, that's fine. I appreciate the question. And I cannot have any substantive discussion around pricing per se. What I'd just say is the following. There's a lot of work that we have to do between now and what is our launch date. And the marketplace is actually going to shift as well 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 appropriate pricing, I'll say. That's as far as I can go right now, but more to come.

But 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 course, but I think other than even oral PCSK9s and we hope that we have to -- the drug has to prove itself, but we design 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 all 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. It takes a lot of the weight off of that messaging that -- 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 LDL lowering, our diabetes benefit, our small particle reduction. Even HDL raising, we're not trying to say it has any benefit other than we know it's very safe to have high HDL, that's -- that was just shown at the anacetrapib trial and we 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, it's 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. Yes, we can talk about that. Yes, okay. So break time, right, Hannah?

Yes, we'll take a 5-minute break. There is some additional food down the hall, bathrooms as well, and then we'll come back at 11. [Break]

Fantastic. 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 Johan, we have Jorge Plutzky, who's a Brigham and Women's, Harvard Medical Center. He runs the Lipid Clinic. He's also a very translational great scientist 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 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 -- finding the working with him, 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 time lines for that coming up. So we'll start the discussion with all of them. And I think 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. 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 -- 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, we're 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 -- 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 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 co-pays and co-pay cards and all that stuff. And so fast forward 10 years, we've seen a big improvement. And now we all have systems in place to write for branded drugs. And with the diabetes classes of agents. Everybody is getting GLP-1s, SGLT2, 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, do you want to?

Yes. It's an issue. We've also wrestled with and tried some novel strategies to overcome and that does gives us some sightlines 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 bad sources of information, social media, Internist sorts of things. Education. I have patients who come in demanding a statin. I have other patients that I can't convince to take a statin, sometimes that correlates with access to medications and undertreatments and bias of education levels of 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 is also an element related to the therapies for example, I have 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 is -- has had 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 components of why people aren't getting treated enough and more aggressively that can help address that. We also have important barriers related to cost and prior authorization and 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 spectrum of these different inputs, whether it's doctors who don't know, of patients who have misinformation, cost, bad sources of information.

Ashish, yes.

Yes, and I agree with everything there. I would 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. Let me use 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 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 would kind of serve those patients. Again, we're talking about a tertiary health care system. But yes, again, just to back that up, it's the patient hesitancy side effects all the misinformation on the Internet about statins compounded with the accessibility issues of now the non-statin therapies again are contributing to kind of the trends we're seeing.

Johan, do you want to -- anything to add, Johan, on...?

No. I think in Europe, of course, the situation is highly different when I listened to BJ 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 BJ'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 PCSK9 monoclonal to live longer, that kind of approach as well, I think, really help in this marketplace.

Yes. I mean, I think we're -- we in Lipid Clinic see a little bit of a skewed view, but I would say, the vast -- 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 total par ApoB. A lot of it is reflecting the Peter Attia, the podcast that we hear. Do you hear similar things in your Lipid Clinics as well? Maybe Ann Marie you want to start there and...

The Peter Attia thing has actually been kind of great because he talks about ApoB and statins and people are coming asking for more lipid-lowering therapy, which has been fantastic. And so finally, we have something in the mainstream that's good for lipid lowering. I just -- I want to briefly mention on the payer thing because we had -- I -- we -- the PCSK9 launch was a disaster because of the payer issue. And I think Regeneron, Sanofi, Amgen just did not appreciate the degree to which payers could impair physicians' ability to prescribe drugs. And 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 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 reject 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 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 would chime in with some of our experience that I think makes me a little bit hopeful about the future as new medicines come along and an increasing intension to the idea of implementation science. And our system is incredibly antiquated 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 that the doctors 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 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 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 is that doesn't involve a physician. The physician expert wrote the algorithm, but a college education person is the navigator who executes it and you start calling people and contact them and saying, you had coronary bypass 3 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 -- and when we do that at scale, of course, 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 that you can actually do implementation at scale much more effectively, including using drugs where the internists 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 undertreatment, some of the barriers and some of the ways to overcome that, that I think had me optimistic that maybe we can get to better treatment.