Global Biopharma Conference with Lee rink. My name is Roanna Ruiz. I'm one of the Senior Biotech Analysts here, and it's my pleasure to welcome CEO of NewAmsterdam, Michael Davidson. Thanks for coming. Thanks, Roanna. Yeah, it's good to have you. So maybe to set the tone here and to start with some bigger picture questions about the company, could you just give us a little bit of an overview about what differentiates your company and your lead asset, obicetrapib, and some of the things you have to look forward to this year? Sure. Thanks, everybody. Thanks for coming. So NewAmsterdam Pharma, we're developing obicetrapib, a CETP inhibitor, cholesterol transfer protein inhibitor. It's a drug that's very potent. It's only 10 milligrams, is 99% effective at inhibiting CETP. And CETP has always been a very exciting target for reducing cardiovascular risk. And we know that animals that lack CETP have very high HDL and very low LDL. And so it's always been considered a target to try to raise HDL. And that's what the four previous CETP inhibitors focused on. But for us, obicetrapib, it's all about the LDL lowering, because that's where the data supports the benefits of reducing cardiovascular risk. And so we have a very potent CETP inhibitor that throughout our phase two trials lowered LDL by 43%, LS mean. And now we're in very late phase III. We'll have our phase III readouts over the next few months. Great. Sounds good. So you might have alluded to this a little bit, but top priorities for the company, you've got phase III readouts coming. What are you looking forward to there, and what should investors focus on? So this is a drug that is very much needed in the unmet medical need for add-on to statins or replacing statins, because these patients on statins, we know that further lowering of LDL does provide a cardiovascular benefit. But what statins don't do very well is actually they raise Lp(a) and other exciting targets that obicetrapib lowers significantly in the 40%-50% range. They increase the risk of diabetes. This lowers the risk of diabetes. And statins primarily lower the larger LDL particles and less so the small particles. And so we have a drug that lowers small particles by 90%, total particles by 50%, on top of statins. So these studies are all on top of statins, primarily. Over half are on high-intensity statins, and many of them are on ezetimibe, and some of them are on PCSK9 inhibitors, especially those that have familial hypercholesterolemia. So the first trial, the readout, those that have autosomal dominant familial hypercholesterolemia, a very important genetic disorder that leads to premature heart disease. This has 350 patients, and we're going to look for primarily LDL lowering on top of great standard of care. A large percent are taking ezetimibe and, of course, statins and PCSK9 inhibitors. So it's going to be showing the benefit on top of those other agents. Again, our baseline LDL is 120, which is great, because the higher the baseline, the greater you can show benefits, further incremental benefits. That's our first trial. Then BROADWAY is our larger phase III trial that's going to have 2,500 patients, primarily with atherosclerotic cardiovascular disease, high risk. And that study will look at, again, LDL lowering on top of statins across the spectrum of high-risk patients. You can see all kinds of subsets of patients, those with diabetes or high Lp(a) or triglyceride elevation, all kinds of different types of cardiovascular disease. And so that'll be a really important study for not just efficacy, but safety and then strength of the data in all those subgroups. And we'll have the top-line data at the end of this year for LDL lowering at week 12, which is a 52-week study, but the primary endpoint is at week 12. Got it. Okay, great. And just building upon that, so with these two readouts, BROOKLYN and BROADWAY coming, how could some of the data points coming out of those trials help build the case for commercialization of obicetrapib and broader use of obicetrapib? Sure. But what doctors want to see is really three parameters that all sync up to cardiovascular benefits: LDL, of course, cholesterol, non-HDL cholesterol, which is a little bit better, and then ApoB, another important marker. Obicetrapib lowers all three quite robustly. And you can correlate, and depending on how you want to do it, LDL has got the strongest piece of evidence behind it, but so do the other two parameters. So what BROADWAY, in particular, will show is that in a very similar population, the amount of LDL lowering, the absolute LDL lowering, and that can be very much plugged into the expected relative risk reduction in our outcome study called PREVAIL, which is 9,000 patients, all with established cardiovascular disease that will finish enrollment by the end of April. Randomized, we can actually finish enrollment by the end of the next few weeks, and then we'll close randomization at the end of April. We have that study is obviously the biggest inflection point for the company is going to be PREVAIL, and that'll finish enrollment. BROADWAY will be very important for modeling what the benefits would be. And because of all the learnings from all the other trials, we now know that one of the key things to really support a great clinical benefit is to have, first of all, the highest baseline you can. Ours is over 100, have the most robust absolute LDL lowering. Ours, again, if we're in that 40% range, we would have at least roughly a 40 mg/dL drop in LDL, which if you look at many trials, 30, 40+ trials, that should correlate to a 22% relative risk reduction. And so, again, you take haircuts for certain things, the loss to follow-ups or people that drop out of the trial. But we have, again, very, very successful in our execution of these trials. We're having excellent quality metrics. So we expect to see that this LDL lowering in this type of study should translate to a very substantial, robust clinical benefit when PREVAIL finishes two and a half years following the last patient enrollment. Again, the length of time is critical to make sure we don't shortchange the trial, to get the time needed to see the benefit established in these high-risk patients. Got it. Just digging in a little bit more, so you mentioned possible enriching of the patient populations in some of these trials, like higher LDL baselines. Also was curious if you could recap some of the powering or the assumptions that are going into BROADWAY and BROOKLYN that give you a bit more conviction? Right, right. So you look at all the trials that have been done, again, the best predictors of benefit are absolute LDL lowering and baseline. Above 100 LDL, you get your greatest benefit established. Much of that may be driven by the better absolute LDL lowering, because the higher you start, the greater you can lower absolute. But clearly, above 100 is shown to have a better chance of showing mortality benefits in these trials. So we have that with our PREVAIL trial. We're going to have this robust absolute LDL lowering, but we also enriched the trial in multiple ways. One is we looked at patients who in the previous trials did, in fact, have a greater relative risk reduction in the CETP inhibitor class with the Merck and ezetimibe. And that was high triglycerides, low HDL, high Lp(a), diabetes. And so those are all risk enhancers. So if your LDL is not above 100, but it's above 55, which is the threshold in which you want to add another to a statin, they have to have these risk enhancers present. So also we looked at what parameters diminish the benefits of LDL lowering, and that is primarily heart failure. So if you have heart failure, if you look at, for example, the ODYSSEY outcome study with Praluent, the relative risk reduction was 15% overall. If you took out heart failure, that risk benefit was a 22%, a very substantial benefit by taking out only about 10% or 20% of the patients. And so we took out heart failure, excluded those patients. Because the point is it's probably too late for LDL lowering to have a benefit. They die of other factors that aren't lipid-mediated. So we wanted to find factors that enhance lipid lowering as a benefit, and we wanted to remove factors we knew would diminish the benefits of lipid lowering. So that's how PREVAIL was set up in advance to maximize. And of course, we want to make sure we go long enough so we have a two and half year minimum follow-up after the last patient is enrolled. Because we know that after the first year, your benefits are very modest, and they start separating out, especially by year two, everyone's achieved the greatest benefit. And so, for example, again, in the previous trial with Repatha, they went only 2.3 years overall, 15% relative risk reduction. But if they took people that were on the drug for at least a year, the landmark analysis, that 15% went to 20% relative risk reduction. So just a year would have made a big difference. We're going to go two and half years as our minimum follow-up for the patient in the trial. Got it. Okay, super helpful. Maybe thinking about the class and the history for a second. Obicetrapib is a CETP inhibitor. We know in the history there have been some failures in the past of the class. How are you thinking about that backdrop and that history of the class? Gotten this question from investors before. Could it be a class effect? Are some safety concerns there, or is it more molecule specific? Well, we know that torcetrapib was a molecule specific issue. The drug raised blood pressure. Even in animal models, a rat within hours, the blood pressure would skyrocket and give it to a rat. So it had a very prominent blood pressure increasing effect, which translated into humans as well, very rapid increase in blood pressure, clearly not related to the target because the rat does not have any CETP. So that was an off-target effect. But I think in hindsight, if everyone was in a rush to get an HDL-raising drug out there, because HDL was the holy grail, the so-called good cholesterol, I put that in parentheses because we now don't use that terminology anymore, because at the time, it was thought that, well, every 1% drop in HDL meant a 3% increase in cardiovascular risk. So it's thought to be protective if you had higher HDL. And so that led people to really focus on the HDL-raising effects. And so the next one, the Roche drug, had no LDL lowering at all. It raised HDL by 30%, 40% and went to two large MACE studies. And it kind of got there on the MACE defense, but not statistically significant, very safe. It showed a diabetes reduction benefit, which is clear even for obicetrapib had that benefit. So the HDL-raising does have a benefit. And what they found was no MACE benefit without LDL lowering. Got it. Interesting. Okay. Then evacetrapib was the one that had the, again, focus on HDL-raising. It was a very short study, just two years. It was safe. It actually had a total mortality benefit, but no MACE benefit. We now know that when Merck went beyond two years, lines started separating after year two, and it worked, and it showed a benefit exactly as expected. In fact, it was better than expected because it lowered LDL. The problem with that trial was they started off with extremely low LDL. 61 was the baseline. Because again, we're focusing on HDL-raising, but they had a very large study powered enough to see a benefit on MACE for lowering LDL. So lowered LDL by 17%, 11 mg/dL drop in LDL, 9% benefit. The predicted benefit would have been 6%. So it was even better than expected. If you took the highest third that had the highest baseline LDL non-HDL, the actual benefit was 17%. And that was actually better than expected as well. So for an LDL-lowering therapy, it actually worked as well, if not better than expected. And so we're trying to, that's why we designed our trial. It's the same drug class, go longer, show even more prominent LDL-lowering benefits. That trial was already well-validated, very large trial showing how safe the drug was, but also it does, in fact, reduce MACE if you use it in the right patients. Yep. Got it. Okay, great. And so looking to the future a little bit for obicetrapib, how are you balancing timelines in terms of an NDA filing? I'm assuming that you get good phase III data later this year and kind of balancing that with possibly having outcomes data in hand as well for commercial launch of obicetrapib. Right, right. So the last point is the most important. We believe it's very important to have outcome data in hand at the time of launch. So when we do the timing, again, we're going to finish enrollment soon. You go two and half years. So we finished the trial at the fourth quarter of 2026. You got some data collection and cleanup time. And so we get the data. So we want to time the filing for LDL that we have to discuss with the FDA. When will they be can we submit the top-line data from the outcome study to the FDA for them to review? So we don't exactly know when in that review cycle that would be, but we want to discuss with them how to proceed with that. We see a modest delay in filing, like three to six months is our base case. Therefore, the PDUFA date would happen like three to six months after the outcome study is already in the public domain. Yep. Got it. Okay. Is there historical precedent for other, let's say, orals or cardiovascular agents that have launched with outcomes data in hand, or it reads out later that actually helps boost the uptake of the product? Well, in the statin world, when we had statins, as soon as the 4S trial came out with simvastatin, that was the very first trial. The use of simvastatin drove dramatically post-outcome data. It was still good before that because LDL lowering was thought to be a benefit. But all the other statins did not have any outcome data prior to launch, including Lipitor, did not have any outcome data until well after launch, and it did extremely well without outcome data. Now, the world has changed. Ezetimibe did very well without outcome data, but then it got into trouble with an imaging study. And so then the outcome study did come out, but right before the drug became generic, actually. And so that's always been a factor. And ezetimibe is now starting to pick up quite robustly. People kind of look back and think about that trial that it did, in fact, work. But the PCSK9 inhibitors started off their launch without outcome data, and they struggled. And the outcome data did help, but the outcome data wasn't as impressive as people had hoped. Again, a couple of mistakes that we're trying to avoid. They went very short on the trials. And the relative risk reduction was only 15%. I mentioned Repatha would have been if they just would have had a one-year minimum follow-up. They would have had 20% instead of 15% relative risk reduction. So we want to learn from those mistakes and, again, maximize the chance for the drug to look the best clinically when we go to market. Yep. Got it. And you alluded to this in the beginning a little bit. So obicetrapib can hit multiple markers of cardiovascular risk, like LDL, and you've got Lp(a). Maybe zooming in on Lp(a) for a second, how are you thinking about that possibly contributing to obicetrapib's efficacy and potency, and just how are you thinking about the overall landscape there with agents targeting Lp(a)? Yeah, so Lp(a) is an exciting target. In my lipid clinic, I still see patients four days a month at the University of Chicago. It's probably the most common referral now of patients. At least a third of patients are coming to see me because of high Lp(a). They're very concerned about it. Most of them have family histories of premature heart disease. So it's getting more and more known. And we're going to have data, outcome data soon with HORIZON, with Novartis's ASO from Ionis. And so that data will be very important for us. Now, we're not trying to get an Lp(a) indication because that's going to be people that have very high Lp(a)s and bring it down to basically normal. But we believe that in the majority of patients that have cardiovascular disease, Lp(a)s are still often elevated, but not to the level where an RNAi or an ASO would be indicated. So let's take a number. Let's say they want to look at 100 nmol per liter as the threshold for an injectable. Anywhere between 50-100 still has high risk, where obicetrapib could fit in very well for those patients. Even those that have higher than that, they all often need LDL lowering anyway. And so choosing a drug that lowers Lp(a) would certainly be attractive to people that have high Lp(a) at baseline. So I mentioned statins raise Lp(a). This drug would lower Lp(a). And that, I think, is a very big differentiator from any other lipid-lowering therapy. In the Repatha Praluent trials, PCSK9 inhibitors, in the high Lp(a) subgroups, the drugs did do better. In REVEAL, with the obicetrapib CETP inhibitor, the high Lp(a), the highest quartile, also seemed to do better. So we think the data will come from PREVAIL as well. In the high Lp(a) subgroup, obicetrapib, based on previous data, should do better. So we're hoping to see that data when it comes out. We could use that as a way to basically enhance the use of obicetrapib in those patients that have modestly high Lp(a)s and high LDLs. It would be a perfect drug for those patients to get them to their dual targets. Yep. Interesting. Okay. So let's say everything works out. You have positive phase III data. Obicetrapib gets commercialized. I guess, in your view, who would be the early adopters among physicians who would want to try obicetrapib first and prescribe it to their patients? And what are you going to do to help educate the other physicians to get them more excited about the therapy? Yeah. So it's interesting. Of the 100,000 doctors that are prescribing statins, only about 10%-15% write branded drugs at all. And then we have a lot of high-prescribing statin users who write no branded drugs whatsoever. I mean, and then we have some early adopters. We know who those doctors are, cardiologists being a large chunk of them, like myself. But primary care doctors have never had a drug like this. They've never had a drug that was highly efficacious, well-tolerated, had this kind of profile, all the other attributes like Lp(a) lowering, diabetes benefit. Even raising HDL resonates with primary care doctors based on our market research, even though we don't think that's a benefit for MACE reduction. But it's still part of the thinking of cardiovascular risk reduction. We think all these factors are going to make this drug very attractive for primary care doctors. Our objective in all our commercial launch readiness is to make sure that we can maximize access for patients with payers. That's why we want to wait for the outcome data to have that in hand when we launch the drug. Got it. Okay. So we also noticed there have been some recent FDA label expansions or extensions for marketed products like bempedoic acid, inclisiran, etc. How might that be a possible tailwind for obicetrapib? And what does that suggest about how the FDA is thinking about the space? Right. It's very interesting, actually. It's a very nice change. Timing is good for us. Timing is good for us for many reasons. One is the guidelines got revised in September 2022. We've seen since then major growth in ezetimibe 18% per year. Statins are growing. Branded injectables are growing. Repatha is going to be over a $2 billion drug. So that benefit is really nice to see in the market. But the FDA also has stated publicly that they're concerned about payers using labeling to withhold coverage. So they brought in the labels. First, LEQVIO, our RNAi for PCSK9, has a primary hyperlipidemia. No longer this indication you have to have max tolerated statins for LDLs that are too high with FH or raised ASCVD. Zetia got a broader label, which is nice to see. Then bempedoic acid as well got a broader label. So we see this broader label as a trend the FDA is going to pursue. I think for us, again, with our strategy of not launching until you have outcome data, that'll help us be in a better position to get that type of label as well. We have to discuss with the FDA, of course. But the more evidence we can show both safety and benefit, the more likely we'll get a label like that as soon as we can towards launch, yes. Got it. Interesting. Okay. And I've gotten this question a lot, so have to ask. So thinking about the competitive landscape, we know that there are other agents moving up the pipeline. And thinking about oral PCSK9s, for example, that might also enter the market around a similar timeframe as obicetrapib. How are you thinking about the treatment paradigm evolving with multiple new agents that could lower LDL? Things like that. Right. Well, we really are appreciative of Merck investing a lot in oral PCSK9 as is AstraZeneca. Again, they see the value of an oral therapy, and that's great. And also enhancing the commercial marketing of need to treat and the lower, the better. All those messages are very important to build a market. However, again, we feel that our drug's profile, especially at launch with outcome data in hand already, takes away any of the concerns. I mean, so we have outcome data already. Again, we set the trial up to outperform these other outcomes. And again, we can't say until we see it, but we set it up to try to do that. So our outcome data will be in hand. And then, as I mentioned, what do statin users lack as far as benefit? The Lp(a) going up, the diabetes risk going up, the small particles not going down. There's no drug like those other ones do not do what obicetrapib does on lowering their Lp(a), lowering the risk of diabetes, and lowering the small particles. So it's a perfect drug to add to statins. It gets everybody based on our phase II data. Basically, it's a very simple oral add-on. It gets everybody to where they should be, pretty much 90% or so are going to be at goal when they're on this statin plus obicetrapib. And then the added benefits, as I talked about, the Lp(a), diabetes, small part, all those things are going to be exciting attributes that would differentiate that from another oral agent. The other thing about the oral agents that are just more problematic are the food effect and taking it with eating for 8 hours without food for 30 minutes or any other drugs for 30 minutes. So those things are going to be challenging for the dosing regimen, which we're not going to have with our drug. So I think it's great that they're going to be on the market after us, by the way, a couple of years, so we can establish ourselves. But the messaging to clinicians about getting to goal and getting treatment more aggressive is all going to help us as well to make this drug successful. Got it. Okay. Great. And then I want to spend a minute or two talking about another phase II trial they just started, the fixed-dose combination of obicetrapib plus ezetimibe. So how do you think that could help differentiate obicetrapib and help build the value proposition of the product overall? So we saw very exciting synergy between ezetimibe and obicetrapib. Now, when we went into the literature, we found something very interesting. And that is that when you have CETP inhibition, you funnel more cholesterol removal through the intestines as well as the liver. So if you do that with ezetimibe being an intestinal absorption inhibitor, that would make ezetimibe potentially work better. That's what we saw. We expected ezetimibe to provide 20% additional LDL lowering as it does for statins. It actually lowered LDL by 30%. And so that synergy is evident in the clinical data. And then when you also think about getting more cholesterol removed from the body called TICE, transintestinal cholesterol efflux, that can have profound benefit on atherosclerosis. So we're doing more work in that regard to see if the fixed dose combination can not only lower LDL more effectively, but also may have other ancillary atherosclerotic benefits that we need to establish, of course, with new science. But the theoretical value is there. And we can see that. And we're going to show more about that first in preclinical studies and then hopefully in clinical trials. So we want to make this into the Entresto of lipids, where you have two drugs that individually are great, but even better is the sum of the two when it comes to modifying, in that case, heart failure, but in this case, atherosclerotic risk. And we think that's going to be an exciting element of that fixed dose combination that we're going to continue to develop scientifically. Got it. Okay. And I also noticed you recently raised funds, so in a much better position now. How do you plan to deploy those and just continue investing in the portfolio and obicetrapib? Where are you thinking there? Well, part of it is developing this fixed dose combination science. That's not a big factor. The other is we do have Alzheimer's proof of concept data that look very encouraging. We're going to see more data after BROADWAY. We embedded in that study kind of a look at Tau and amyloid plasma biomarkers, which our experts tell us if those show the right direction, like what we did in the proof of concept study. That'll be very powerful about obicetrapib's benefit on ApoE4-related, which is the majority of people with Alzheimer's disease. Those are modest amounts of money. But primarily, we think the financing takes all future financing risk off the table. And so if we have great phase III data, which we're expecting, that'll allow the stock to meaningfully move up without anyone thinking we're going to do another financing on top of that. So we think this is strategically important. But it also gives our Chief Commercial Officer, BJ Jones, who launched Nurtec very successfully for Biohaven, more ammunition to get the market ready too. Because we think, obviously, it's a big market. We know who the doctors are. We have to target. We know the KOLs. We want to invest a lot in market development because no matter whether we do it ourselves and launch the drug, which we love to do, or if we find a partner, M&A strategic, the more we can prepare the market and show the value of that, the greater the transaction will be for our investors. Okay. Great. And I want to ask a slightly different question in the final minutes. So thinking about GLP-1s and their impact on cardiovascular space and possibly obicetrapib if it also gets commercialized, how do you think that interaction might happen in terms of the market landscape? And could they actually coexist together in the treatment paradigm? I think they can coexist together very well because GLP-1s address weight, but they don't affect LDL at all. And they lower the risk of diabetes substantially. So does obicetrapib. And so in the world of prevention, which I'm in, I mean, I can see a combination of an oral GLP-1 with obicetrapib. And that would be a drug that would you lose weight, you lower LDL dramatically, lower Lp(a). Your diabetes benefits are additive on prevention. And so you can see a world where you can basically prevent all heart disease with that type of combination, especially the American population, which we know is overweight and has very high LDL. You need both to really get the risk out for patients. Skinny people still have a lot of heart attacks. And then obese people, when they lose weight, still have high LDL. I think both are a really important part of the treatment armamentarium for reducing risk. Good to know. Great. So I think we're at time. But thank you again, Michael, for coming and talking about your programs. Thank you, Roanna. I very much appreciate you having us here. Likewise. Thank you.