Good afternoon, and, thank you for joining the Guggenheim Securities Healthcare Team at our sixth annual conference. I am Debjit, and, joining us from NewAmsterdam Pharma are Dr. Michael Davidson, CEO, President and CEO, and Ian Somaiya, CFO. Thank you both for your time, and, Michael, if you could just give us a very quick overview of obicetrapib? Sure. So obicetrapib is a CETP inhibitor, cholesteryl ester transfer protein, and it blocks the transfer of cholesterol from HDL into LDL. So consequently, it's a very effective way to lower LDL, raises HDL. We're excited to have this molecule. It has very special features that make it, you know, very effective at lowering LDL and also at lowering Lp(a) and other things that reduce cardiovascular risk. Awesome. So 2024, you're gonna get data from the BROOKLYN study first and the BROADWAY study second. Right, right. The BROADWAY is probably the more important study with 2,500+ patients. How do you think you're going to leverage the BROADWAY data to inform the PREVAIL study? Sure. So, as you said, it's 2,500 patients. The majority have atherosclerotic cardiovascular. It's almost, basically the same population as PREVAIL, and it's a one-year trial, and so I think there's really good ways to model the absolute LDL lowering from that trial. You know, should basically be the same as the absolute LDL lowering in the PREVAIL trial. And then, we have a very well-known association between the absolute LDL delta reduction and major adverse cardiac event reduction, as long as you factor in time, which is what we've done in our trial as well. So we designed PREVAIL to make sure the trial not fail the drug, and one of our important theses of our whole company is not just a better drug, but a much better clinical trial program to highlight the advantages of that drug for patients. Got it. You know, going back to the first question on obicetrapib, could you walk us through where you are, or where you think you're gonna be on the LDL lowering side, on ApoB? Yeah ... as well as Lp(a), which seems to be a very differentiated factor for obicetrapib. Sure. So if, if you think about other CETP inhibitors that were developed, unfortunately, unsuccessfully, the, the LDL lowering is in the, in the, in the 20% range. Lp(a) lowering is also about 20%, at best. So we, we have a drug that lowers Lp(a), LDL twice as much, Lp(a) as well, twice as much. So we're talking in the 40% plus range for the LDL and, and, and Lp(a). So far, in two trials, 47% in one and 57% mean reduction in another. So we're hoping it's gonna be similar to that, you know, kind of double the, the efficacy as we saw from, from other CETP inhibitors, which is roughly 40% plus for LDL and around 40% for Lp(a) as well. Got it. And, depending on the BROADWAY readout, do you think you need to make any changes to the PREVAIL study, or you're sort of happy with, you know, the kind of patients you've enrolled, the duration of follow-up, and et cetera? No, we don't think we need to make any changes to PREVAIL, but we do have that flexibility, and the one thing we have the most flexibility on is going longer, and to get more separation, time to separate the curves. There is a sweet spot, when you... 'Cause as these trials go on, you've got to keep maintaining compliance and follow-up and everything, and so I think we believe we found the right Goldilocks approach for these trials, which is not too short, which is, you lose a lot of benefit in the first year, in particular. And so two and a half years minimum follow-up, we think gives us the maximum ability to show the best relative risk reduction for, you know, roughly a 40% LDL lowering. So getting back to BROADWAY for a second, I think what I would take out of it, again, being a cardiologist, lipidologist myself, the absolute LDL delta from BROADWAY, we're hoping is in that, you know, roughly 40 mg per deciliter range, which we know from all the other trials correlates with a 22% relative risk reduction when you look at the totality of the data. Again, the trials are different, length, populations, and so forth. That's the rough number that everyone models. You look at all the trials, you come up with that correlation. And so BROADWAY, if we get to that level of delta on LDL, or close to it, 38 mg per deciliter, which is the exact 1 mmol, then we should expect, if we can obviously execute a really, really well-done PREVAIL trial, which we're so far seeing, you know, really great metrics for PREVAIL on tolerability, dropouts, everything is going really well for PREVAIL. Then we should see the same, that relative risk reduction in that 15%-20% range for PREVAIL. Got it. So let's talk about PREVAIL, and, you know, walk through the different parameters that have... that are unique and different in PREVAIL. Start with LDL-C baseline. I believe you're at 105? Right. How does that compare with all the previous CETP? Well, much higher because the one that was the most largest was 30,000 patients in REVEAL, which was the baseline LDL was 61 mg/dL. Fortunately, it worked, and the highest tertile, which is 10,000 patients, it lowered non-HDL LDL by 22 mg/dL, and that resulted in a 17%-18% relative risk reduction. So the correlation actually worked well, if not even better than expected for anacetrapib in REVEAL. And I think that it could be, we can't say for sure, but it could be 'cause the added benefits that the CETP inhibitor class has on Lp(a) and small particles, those other attributes, raising HDL, that might also contribute to a benefit. So, that's kinda how we see it, that PREVAIL is designed to, you know, basically mimic that upper tertile of the anacetrapib trial, the REVEAL trial. So we did add to what. We looked at other—who benefited the most from CETP inhibition in REVEAL? And that was the higher baseline, we got that, the higher baseline LDL, non-HDL, ApoB. High Lp patients did better. High triglyceride patients did better. Low HDL patients did better. So we enriched the study to have those type of patients in there because you—if you're over 100, you get on the study automatically. If you're above 70, you have to have one of those risk enhancers to get in to the trial. That's, again, we think that's what, why we wanna keep emphasizing the point that it's not just a better drug, but a better trial to highlight the advantage of that drug for clinicians when the results come out. Got it. And you sort of touched on it before from a duration of follow-up perspective, PREVAIL will have the highest median follow-up of 3.5 years? Median 3.5 years, but a minimum 2.5 years. Right. So that- With the option of extending it further, right? That's the optionality Michael spoke to earlier. Got it. How does that duration of follow-up match up against some of the other studies that you- That's, that's the longest minimum follow-up of any study in recent memory. So the longest duration of follow-up... The longest minimum follow-up, I've ever seen before was two years. We're going 2.5 years for minimum follow-up. Got it. So- From a primary endpoint perspective, it's MACE? MACE, yes. But you're not including, elective revasc. Right, right. So could you walk us through the nuances there? Right. Because it, it's... Some of it's geographic issues, but, like, around the world, you know, if, for example, we're, we're doing studies in Poland and so forth. If you have a, if you have an unstable angina, an MI in Poland, you go to the hospital, they call your bank, see if you have enough money for a stent, and they, and they, and they, and they... Then, then they'll release the stent from the hospital, you know, formulary, whatever the, where the stent's located. In the U.S., you go to the, get a CAT scan of your heart, and it shows calcium. They get a stress test that's positive, and you, and you get a stent. It's, it's not a symptom-driven, urgent revasc, which it looks like when you look at all the data, again, it's, it's... When you look at what really does LDL-lowering prevent, it's the urgent revasc. Again, if you look at the REVEAL trial, urgent versus non-elective, the relative risk reduction was greater for the urgent revasc. So we picked urgent revasc as our main endpoint for the trial. Of course, we have the traditional endpoints, which is cardiovascular death and stroke, you know, non-fatal MI, non-fatal heart attack. Go- So, but an urgent revasc is getting more and more accepted as the better endpoint to include in these trials. That's why we use that as our 4-point MACE. Got it. And in terms of, you're also excluding heart failure patients, right? Right. Right. If you look at the FOURIER and the ODYSSEY studies, I guess it's a learning from that, to exclude heart failure patients? Yeah, very much so. So if you look at, let's give you, I'll give you the ODYSSEY OUTCOMES as a good example. So it had, I think, 14,000 patients, of which 2,000 had a history of heart failure. When the trial was over, it had a 15% relative risk reduction. When they took out the 2,000 patients with a history of heart failure, that relative risk reduction went to 22%. So it was diluted by the... And the heart failure, by the way, had over, has a ratio over one, if they got alirocumab. But I mean, but again, it was probably not harmful, but it was not, certainly not helpful to have LDL lowering, and somebody had a setting of heart failure. And so we have taken that out for the same basic reasons. We wanna maximize the patients that we know benefit from LDL lowering, but also remove patients that we know don't have benefit from LDL lowering from our trial. Got it. Just to sort of reframe, then, the BROOKLYN and BROADWAY, it might inform the duration of follow-up, or can you change anything on the primary endpoint as well? Well, we can. We have time to do that, and we would consider that if data does change. I mean, there are other outcome studies that are reading out, especially the Lp lowering trials. If we find that it affects revasc overall, we could consider modifying that. That's the only endpoint we really could modify, the revasc endpoint. But duration is the best way to do it, the best way to show, you know, more events over time. Again, revasc is changing also, even in the U.S. There's much less elective revasc than there ever was. I mean, it's getting to be a much more symptom driven decision about giving somebody a new stent. The safety profile to date has been very clean. Yes. So are you sort of monitoring blood pressure changes in the BROOKLYN and BROADWAY- Yes ... studies on a real-time basis? Yes, we are. We're always monitoring that, blinded, though, and we did release our blinded safety data back in June. We had 1,000-plus patients or so at the time, and we saw no effect on blood pressure with 2-to-1 randomization. So if there was any, and it was completely flat, no, no, no blood pressure effects. Of course, it's in phase II, no blood pressure effects. So we're confident that there's very little, if any, blood pressure increase with obicetrapib. With the 9,000 patient kind of enrollment, that should be wrapping up relatively soon? Yeah, very... This quarter. Are you anticipating any PCSK9 drop-ins in the study? We're not really, because we haven't seen it so far. And basically, if you look at even in the U.S., the market trends, I mean, we're seeing very little penetration of PCSK9 across the world. We're mostly outside the U.S., where access to these drugs are only limited to those that have familial hypercholesterolemia. So we don't have those in our trial, in our PREVAIL trial. Got it. And in the ACC meeting, the Novo SELECT study had some effect- Yeah ... of COVID. Are you sort of anticipating anything in PREVAIL? Well, we're preparing for that. You know, we have, you know, we obviously have to have contingencies. We're ready, you know, we're ready with remote monitoring, shipping drug as needed. So we're preparing for any type of COVID pandemic situation. Again, I learned a lot from what happened with COVID in a few years ago, about how to conduct trials during that, you know, during that unfortunate period. So we will, we'll prepare for that as we go along. You will be in a position to file the NDA sometime in 2025, following BROOKLYN and BROADWAY? Right. Walk us through sort of how you're thinking about this commercially, given that PREVAIL will read out in 2026? Right, right. So we'll file in Europe. Europe is a different scenario there because Menarini is our partner. In Europe, you file, you get approval, and then you have a one-year period where pricing is established by the company, and then the government can come in and reassess. You know, so that, for that one year, they can have the outcome study read out a year later, and not be an issue 'cause that's when they need the data one year after launch. But for the U.S., with payers, you wanna have the data at the time of launch, and we also wanna have the fixed-dose combination available at the time of launch. Remember, the fixed-dose combination, if we're in the 40% range with the mono, we should be in the 55%+ range with the combo, based on our ROSE2 data. So we wanna have both at the same time because we're seeing the market growth on ezetimibe use anyway. In fact, in our trials, you know, we have 20% on ezetimibe in BROADWAY, and we have 50% on ezetimibe in BROOKLYN. So ezetimibe use is growing, so we take advantage of that with our fixed-dose combination, having that available, so they easily go from one pill to another during our launch period. Now, that launch is, again, we wanna have the greatest drug possible, the best trials possible. Also, wanna have the greatest launch possible, which means we're gonna have everything lined up for launching successfully, which means we're already got a chief commercial officer who's very well known. He launched the Biohaven Nurtec drug, one of the very few successful launches from a small company. And we're also starting to engage MSLs in the marketplace, starting now. We're getting MSLs lined up to prepare the market. And what we wanna do is we wanna, you know, file the LDL indication so that the outcome study reads out before the PDUFA period. So if the study's ending in end of 2026, we want, we wanna make sure that the answer to the REVEAL, turning the card over. Sorry, PREVAIL does not happen until during that PDUFA period. So we wanna time the filing accordingly. We have a year of the review period of time where we could potentially file the LDL indica- during the f- give them the PREVAIL data to review. So- And then, and just, just to complete that thought, we're in a unique position to be the first company to launch with both LDL and outcomes data in hand, and that provides benefit from a payer access standpoint. And if you look at the space today, it's, it's been profiles of drugs that have been suboptimal, but it's also been payer access that's restricted usage. Got it. For a company of your size, as a cardiologist, what kind of MACE benefit would you like to see, where the drug sells itself, and you don't have to sell the drug? Well, I think we wanna see... Well, 15%'s the bar. Like to see more, of course, but as long as the drug works as expected, which is 15%, when you factor in all the factors, like this, you know, the drop-in, the dropouts, which is, you know, that's the... All the things you have to consider in a trial like this. Well, you know, we have very low loss to follow-ups, but you gotta... In an all-comer study, you have to basically, you're basically doing intent to treat. I mean, so you have to live with what you have, and that can... At the end of the day, 15% would be a great result and show a benefit there. Again, we have the opportunity to maybe do better based on how we designed everything, but that'll be upside for us. Yeah. And- Maybe the other way to think about this is three-quarters of the patients today that are being treated remain 20% above their goal. If you look at just the simple LDL reduction that we have shown in our phase II studies, and if we replicate those, we can get vast majority of those patients to goal. Got it. How big a sales force do you think you would need to successfully launch this? Well, we're looking at that now, and we have a very good team. A great team, actually, just coming on board. We're gonna look at two different options. One's a skinny launch or a big launch, and we're looking at both options as a company. And then, again, at the end of the day, if we do get acquired, all this work that we're doing to build value for the drug in the commercial market will bring value to the company. So that's our... We're preparing the market for launch, and we're starting now. Got it. So walk me through the skinny launch versus a more, you know, broad-based launch. Does that depend upon what the actual MACE benefit comes in at? No, no. Let's say you're at 20%- No, no. Could not- Could be a skinny launch because the drug should sell itself. Right, it should. But, no, listen, I, I'd love to do the big launch, to be honest with you, but- Yeah ... we have to consider, you know, all the issues. Yeah. And we- It's always more complicated than just that, just the profile of the drug. It's really looking at the prescriber base, whether it's cardiologists or primary care, and who are the highest prescribers, and how many sales reps that we need to target those high prescribers. How many would you need to target the really high prescribing doctors? That's a question we'll happily answer in the calendar year 2026. But what's good, though, people don't realize it is a big market- Yeah - but we do know that the high-prescribing branded doctors represent only 14% of the doctors. Yeah. That, so we can potentially do it ourselves in the right setting. But- It's an 80/20 rule, which applies to a lot of different categories. It's also true for LDL reduction. Got it. And anything you can learn from the ongoing PCSK9 launches? I mean, Repatha is- Well, the most important thing is getting payer feedback- Right ... initially, and having outcome data at the time of launch. And that those two lessons, I think, even Esperion, if they could... I'm sure if they could do it over again, would have waited for outcome data before they launched with their profile. So we think those two things in particular are critical. But we want to prepare the market. That's why we're developing the access meetings with all the payers now, because they, we want them to get ready for this drug, 'cause I think they'll see it as of great value for them as well, for their customers. How do you see competition from an oral PCSK9? Well, we think we're two years ahead, minimum, especially if they wait, if they wait for outcome data, we're two years, more than two years ahead. But also, I think what the big, the big positive for us, we'll have outcome data, so there's no, there's no longer this, any of this headwind on whether it has outcome data or not. And, and for the PCSK9 inhibitor, yeah, that they do have that class benefit, 15% relative risk reduction. So, in that sense, our drug, you stack it up, if you look at what we would do on, on LDL, ApoB, non-HDL, Lp(a), you know, LDL particles, prevent diabetes, oral small molecule, no food effect, it, it would definitely beat an oral PCSK9 when you look at the overall benefits of a drug like that. And look, you know this all too well, but there is a significant food effect associated with the delivery of an oral peptide. So requiring a patient to fast for 8 hours, take the medicine, and then wait another half hour for any intake, food, drinks, medicine, that's a hindrance. And when you think about the patient population, where the average age is somewhere in the high 60s, low 70s, when they're not just dealing with elevated cholesterol, they're dealing with lots of other issues, which they're taking medicines for, that's going to play into how that drug is utilized. And that's something that I think we know we all need to be mindful of. Yep. Rybelsus, it does pretty well. I think it's $1 billion in sales, but compared to the overall GLP-1 market, it struggles 'cause but oral peptides are not the easiest drugs to take. Yeah. Got it. And, compliance in the secondary prevention setting is still in the 50% range. Does an oral CETP change that? 50% compliance? Yep. Listen, I think, I mean, look, I can't, we can't speak to the phase III data that'll come out, but I would say based on the phase II data, we have a very well-tolerated drug, very well-tolerated, including patients that have not tolerated statins before, 'cause we have about 10% statin intolerance in our trials. This drug is what we're seeing, a very clean safety profile based on phase II, and then as far as discontinuation rates in phase III, we're seeing, you know, low rates. I've never seen it in my clinical experience of doing a lot of trials, this drug appears to be very well-tolerated. Awesome. We have a few minutes if there are questions from the audience. Going once? Nope. All righty. All right. I appreciate the time, Michael. Thank you. Thank you so much again. Thank you, Debjit. Thank you.