Good morning, and thank you for joining Guggenheim's second SMID Cap Biotech Conference. I'm Debjit, one of the therapeutic analysts here, and joining me from NewAmsterdam Pharma is Chief Financial Officer Ian Somaiya. Thank you for your time, Ian. Thank you, Debjit, and I want to thank Guggenheim for the invitation. It's our second year at the conference. I didn't realize this was your second conference, so we're happy to support it. A lot's changed since your first visit to our conference, so maybe a very quick intro before we get into the Q&A side. Absolutely. You're right, a lot has changed over the past 12 months for us. We've had the opportunity to complete and share results from three of our Phase III studies, and happy to report they were all positive, quite consistent from really every marker that you can look at, whether it's LDL, Lp(a), and probably most importantly to us and our two scientific leaders, Michael and John, the safety. It remains one of the cleanest drugs that they have ever had an opportunity to work on. And as you think about the type of patients that obicetrapib could ultimately treat, these are patients that tend to be asymptomatic, so safety is a good starting point for us. But even from an efficacy perspective, the consistency of the data we've seen and the robustness of the LDL and Lp(a) reductions really gives us a lot of confidence in translating the clinical success to the commercial setting. So that's a good segue then. Given the sequence of BROOKLYN, then TANDEM, and then BROADWAY, how are you guys thinking about obicetrapib's position in the commercial market, especially if you start thinking about the oral PCSK9 competition, which may or may not happen? Yeah, I mean, let me touch on competition and maybe just reframe it a little bit. I think it'll be a disservice to patients and providers, and I would say equally to shareholders if we treat this as a zero-sum game. So as we think about some of the other companies that are developing therapies for these patients, it's an opportunity. It's a rare opportunity to look at the tens of millions of patients in the U.S., 30 million plus, who know they have elevated LDL, who are being treated by a clinician. They are getting treatments for their lipids, and yet are not at goal. So if we treat this as just a zero-sum game, market share, I think it's going to be a disservice to the entire community. I think the opportunity is to make lipid-lowering therapy once again at the forefront and top of mind for every clinician and every patient, and if we do that, we can go back to the setting for this category, for this therapeutic space, which we saw back in the 1990s, where each of the companies was hugely successful, but I think it's sort of a natural question, and it's a fair question, because they are an oral drug. They all also reduce LDL, but I think that's where the similarities end. Our therapy, and we've stated this over and over again, is more than simply an LDL-lowering therapy. We can reduce LDL, we can reduce Lp(a), and as we think about the mainstay in this therapeutic category being statins, we offset the risks that are seen with statin therapy. So if a patient is on statin, not at goal, what's in essence missing? What's going to drive treatment decisions? It's going to take into account the magnitude of LDL reduction that's needed to get that patient to goal. And whether it's OB alone or OB plus mono, we can get the vast majority of patients to goal. It's evaluating the other risk factors that are implied. It's the elevated risk of diabetes when you're on a high-intensity dose of statins. What we're seeing with the CETP class quite consistently, and what we saw in our BROADWAY study data, is we can also reduce the risk of diabetes, and that's something we hope to confirm in the PREVAIL outcome study. When you look at statins, they reduce primarily large lipid particles, so the residual risk that's left, it's represented by small lipid particles. When you look at the available treatments that are out there and the ones in development, they also similarly only impact large lipid particles. So through our mechanism, through inhibition of CETP, we offer that something quite distinct, which is virtual elimination of small lipid particles. And I'm sure we'll get into the Lp(a) side of this, but that's also a very intriguing and critical feature that further differentiates us from some of the competitors. We've seen 40%-50% reduction in Lp(a) quite consistently across our trials, and that's something we think will translate into incremental benefit to patients. You brought up one of the salient features of OB being safety. 12,000 patients at least have gone through OB right now, by my last count. You think OB has finally exorcised the ghost of all the other CETPs? Because that still is a question that we get. Yeah, it's understandable. It's rare in any therapeutic category that you have four distinct programs that were studied, four clinical programs, and ours is the fifth and the one that's likely to be the only one that makes it to the FDA. Obviously, we need to get through the FDA approval and complete our studies. What I would say is Merck did a very good job of addressing a lot of the historic baggage of the class. As you think about unique adverse events, which we're seeing with Torcetrapib, and I say those are drug-specific because what we saw was an increase in blood pressure, which was a result of an increase in aldosterone. As a result, the FDA has asked every subsequent program to specifically focus on blood pressure elevation. In our BROADWAY clinical trial, we had a sub-study where we used Holter monitors, so 24-hour monitoring, to once and for all put that issue to bed, and we're able to do that. We had a clean profile in that sub-study. The other issues we've seen with the class have really been more on what was the question they were trying to answer. And the question was, can increasing HDL translate to an outcome to benefit? And what we can say quite conclusively based on the data from these prior programs is the answer is no. But what Merck, through their CETP inhibitor, Anacetrapib, what it allowed, and I think it ultimately enabled us to continue to advance our program, what it clearly showed was that if you reduce LDL irrespective of the mechanism, the underlying mechanism, you can provide an outcome to benefit to patients. Fast forward to obicetrapib and our program. We're the beneficiaries of not only having a better CETP inhibitor, so we believe OB is a better product. It's more potent when it comes to CETP inhibition, and that's clearly translated to a more robust LDL reduction, Lp(a) benefit. But we're also the beneficiaries of hindsight. We've looked at the clinical programs of the past, not just the CETP inhibitors, but also the PCSK9s, and improved from a clinical trial design standpoint. That gives us confidence that ultimately the data you saw on BROADWAY will translate to clinical success for PREVAIL. So from an efficacy standpoint, we feel very confident that we have addressed some of the prior concerns with CETP. But I think Merck, through their 30,000-patient clinical cardiovascular outcome study REVEAL, already addressed that from a safety perspective. With the Broadway data now in hand, we've met ICH guidelines for safety. We can say with all confidence that we believe obicetrapib offers a safety profile that's comparable to placebo. Got it. So let's touch upon two other points. One is the relative or the 5% delta you saw in new-onset diabetes in the BROADWAY study, and also the Lp(a) component. So when you think about the three-point MACE benefit, what drove that beyond LDL-C? It came as a surprise to everybody. So just thinking through the thought process of what are you guys thinking internally, given Michael and John reside within Guggenheim's? Right. Yeah, so the surprise finding, and thanks for sharing that. I mean, I think we were equally surprised in the MACE signal that we saw out of BROADWAY. What would have been expected would have been, at best, a benefit of 9%. So if you look at the hazard ratio, what would have been expected would have been a hazard ratio of 0.91. What we saw instead was a hazard ratio of 0.79, so 21% risk-benefit at year one. And when you compare that to outcome studies of the PCSK9 and others, the best data we've seen is an outcome benefit of 15%. That was reported with both Repatha and Praluent. So the question is a natural one. What drove that incremental benefit? One of the areas of focus has been on Lp(a), and it's timely because we have several dedicated programs looking at translating Lp(a) reduction to an outcome benefit, and the first data set, which is the Novartis Horizon study, will read out at some point next year. Let me tackle that question in a couple of different ways. Prior to the availability of the Broadway data, what we had hoped to learn from Horizon and our drug's effect on Lp(a) is how much incremental benefit could we expect and PREVAIL based on the benefit that we're seeing on LDL? That was under the assumption that our benefit, MACE benefit, would fall on the CTT regression line. The reality is our benefit was well above the CTT regression line. So now what we hope to learn when HORIZON reads out is what was the incremental contribution of Lp(a) and the effect that obicetrapib has on the 21% MACE benefit that we observed in BROADWAY? And to the additional point that you raised, what is the incremental contribution of the diabetes benefit we're observing? What is the incremental contribution of the LDL particles, which we virtually eliminate? So there are many points of differentiation for OB relative to other classes of drugs, and we're starting to have access to enough data to be able to answer the question of relative contribution to the overall benefit. Diabetes plus the GFR function, which was also another interesting surprise. That's right. When you think about 2025, by mid-year, most of the patients in the PREVAIL outcome study would have been at least on therapy for one year. What's the internal thought process in terms of engaging with the FDA on either changing the primary endpoint or trying to do an interim with a three-point MACE? Yeah, so let me tackle the last part of your question first. There will be no interim analysis of PREVAIL. It makes absolutely no sense to do that. But I understand the intent. I think what we're trying, the question we're all trying to ask and answer is, is there a way to get obicetrapib on the market sooner? An interim would be one way of doing that. It doesn't make sense to do that because we want to maintain the integrity of the study, and we also want to conduct the study once. It's a huge undertaking for our team, and we think we have a design that's basically a larger version of BROADWAY. So think of BROADWAY as sort of a baby outcome study, and given the similarities in the patient populations, we can apply all the learnings from BROADWAY to PREVAIL. One of the controls we can exercise is redefining MACE. We can go from four-point to three-point. Just to illustrate that point, using a four-point MACE, the benefit was 21% in BROADWAY. If we were to apply the three-point MACE, obviously that benefit goes well above that, well north of 30%. That is a control we have, but a decision that we don't need to make now. The earliest we could make that decision is one-year follow-up following the completion of enrollment of PREVAIL. That's April of this year. That's the earliest we can make a decision. The latest we can make a decision is up until data lock, so really at the very end of the trial. What allows us to answer that question is not just simply the event rate, and that's critical. How many events are we seeing for each of the components of the MACE? And once you're at that one-year time point, what we would expect is a fairly straight line in terms of the event rate over the remainder of the trial. But the other aspect of answering that question is really an engagement with the FDA. What does the FDA think of this strategy in terms of redefining MACE to three-point? There's also a commercial question that we need to answer, which is, is there an impact on how payers perceive and providers prescribe Obicetrapib based on the definition we use? So that's work that the commercial team is embarking on today. And as you would expect, at the conclusion of our Phase III studies, we will meet with the FDA and get that perspective. But it's not just simply a three-point versus four-point. What we can say with all confidence is we believe there's a high probability of PREVAIL being successful, and we have the opportunity to exercise some controls, but a decision hasn't been made. Got it. So for 2025, the Obicetrapib regulatory submissions are primarily for Europe. What's holding up the U.S. submission? Yeah, so yeah, so the timelines are well defined for Europe. We're planning to file for approval in Europe in the second half of this year, so launching in the second half of 2026. In the U.S., we have a rare opportunity. There's never been a lipid-lowering therapy with outcomes data becoming available at the time of launch. And related to that is, again, the commercial assessment. How much incremental value is there to having the outcomes data available at launch? So that's a demand study that the commercial team is embarking on now. So I wouldn't characterize it as a delay. It's a decision that we've made to have outcomes data become available at the time of launch. It's a rare opportunity. There's been no other clinical asset in this category that's had that. And we want to make sure we fully capture that because it could contribute to the initial adoption. It could contribute to the overall opportunity we realized during the period of IRA. So there is a commercial component to that question that we're actively answering. Got it. On the delay in the HORIZON Lp(a) study from Novartis and Ionis, what's the thought process now for John and Michael? Is the delay because Lp(a) is six times more atherogenic, and so you've got a dramatic reduction in event rates in the treatment arm, or is the risk not linear like in LDL-C, or the magnitude of Lp(a) reduction needs to be, call it 80%? Yeah, I mean, look, all those are sort of fair options or reasons for the trial being delayed. We would rather leave it to Novartis and Ionis to answer those questions, why they believe the program timelines were delayed. Was it the drug is doing what it's supposed to do and maybe even better than what they had initially thought? Is it related to just the initial sort of calculations in terms of what the event rate would be, and it's simply that? But either way, it's not as critical of a driver for us in our thinking and doesn't really inform us to the degree that we had initially thought were it not for the MACE benefit observed in BROADWAY. So it was really an important catalyst for us before the BROADWAY results became available. Now it's a piece of the puzzle. Really the piece is, what was the contribution of Lp(a) to the benefit we observed in BROADWAY? Yeah, I mean, I think I would leave it at that in terms of the impact of that study. So do you guys think you're going to get Lp(a) on the label as well? Yeah, it's a question with maybe a little bit more certainty in Europe versus the U.S. In Europe, if you look at the label for Inclisiran, Lp(a) is shown on that label, the reduction of Lp(a) for Inclisiran. So we feel confident that we can also have our Lp(a) benefit captured in the label in Europe. In the U.S., we haven't seen it, and maybe it's a matter of time. So maybe with the regulatory, and this is all conjecture, what the regulatory body, the FDA, needs to see is a Lp(a) therapy, reduction of that Lp(a) translating to an outcomes benefit. So maybe it's just simply a matter of time. We don't want to just simply rely on that. As you know, we do have a study, a Phase II study that we're actively conducting now called the Vincent study, where we're exploring the impact of obicetrapib on Lp(a), and then also evaluating the combination of OB and Repatha, PCSK9, on that. And we think there is additive benefit there. So that's a data set that will likely become available later this year. What that could support is potentially a Phase III study looking specifically at Lp(a). But please don't expect an outcome study from us. The patient population that we would likely address is quite dissimilar from the ones the injectables are going after today. If you were to look at the enrollment criteria for the injectable PCSK9s, they represent 10%, maybe at the most 15% of the eligible patient population. What we could likely address is right below that, which represents the vast majority of patients. So that's a study that we're contemplating. No definitive timelines or even commitment to doing that, but that would be a study that would potentially allow us to have a label claim. Obviously, the cardiovascular primary care landscape is complicated. How are you thinking about the commercial launch process? And from payer reimbursement perspective, what's the ideal target product profile for a good reimbursement scenario? Yeah, so let's talk about reimbursement and kind of where we are today and this is based on feedback we've gotten from payers. Payers are very comfortable with the lipid-lowering therapy. They feel, and they've mentioned this to us, that they have very good control over pricing in this category, so it's not pricing, and it's not access. If you look at the access for Repatha, or bempedoic acid, it's pretty universally available today. Even the prior authorizations of the past, which are quite onerous, are now electronic. It's quite easy to get access to a PCSK9, so it really goes to the other part of your question, which is the target product profile and what would resonate with clinicians and patients. So as I mentioned previously, if statins remain a mainstay, and whether it's statins or statins plus ezetimibe, patients are still far 20% or greater above their LDL goals, we think OB is an ideal add-on therapy for these patients, either product form, because it gets the vast majority of these patients to go, because it offsets the diabetes risk that's associated with high dose of statins, and because it reduces LDL particles, the small particles, which statins and the other available add-ons don't, and with the additional benefit of more profound effect on Lp(a). So that combined with the safety profile that we have, we think we're ideally suited to address the vast majority of patients' needs and could, as a result, become a preferred option, therapeutic option on top of what's most often prescribed, which is statins and ezetimibe. Along those lines, in 2024, FDA did update the label, right? It doesn't necessarily have to be in the secondary prevention setting. Yeah. I don't think that implications of that are widely recognized. Could you sort of talk to that? Yeah. This is the FDA, a regulatory body that observed that payers are restricting access to drugs that could benefit patients because of the label, and what they did as a result was, to your point, amended the labels of not just the PCSK9s, but I think bempedoic acid also benefited from this to give it a broader label claim, including primary hyperlipidemia, and this is the same benefit that we would hope to realize, and what this allows us to do is avoid having to run a primary prevention study. The other label update, which is also, I think, quite important to discuss, is the inclusion of the subcomponents of MACE that are now shown in the Repatha label, where the four-year outcome study did not show stat-sig, so despite not showing statistical significance for individual components of MACE, now they are part of the label claim for Repatha. So that's another change that the FDA has made to really allow these drugs to benefit patients to get as broad of an access as possible without having the supporting data. Got it. So just to recap your thoughts on the endpoint change or interim for that matter, no interim this year. Yes. No need to do it. No interim, period. Not this year or next year. No interim, no need to do an interim. Yes. Open to changing from four-point MACE to a three-point MACE. Are you going to make that decision this year, or do you have time all the way before data lock? No, look, I can't be any more clear. We have up until data lock to make that decision. The earliest we would have insufficient information to ponder a change is at the one-year mark following the completion of enrollment. So that would be at the end of April of this year. Got it. And we just ran the clock. All right. Thanks so much, Ian. Thank you, Debjit. Thanks for everyone for being here. Thank you. Good luck. All right. Thanks.