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

Hi, everyone. Good afternoon, and thank you for joining us at the Annual TD Cowen Healthcare Conference. It's my pleasure to introduce the management team of NewAmsterdam Pharma. I'll pass it off to Michael Davidson, the CEO now for opening remarks and the presentation.

Thank you all very much for attending. I'm Michael Davidson, CEO of NewAmsterdam Pharma. Also in the audience is our CFO, Ian Somaiya; and our Head of IR, Matt Philippe. These are disclaimers. So I want to give you a brief overview about NewAmsterdam Pharma. This is a way of background for myself. I'm a cardiologist, lipidologist, has been starting biotech companies for the past 15 years. I also still see patients 3 or 4 days a month in the University of Chicago, run a Lipid Clinic there. So for me, this is a real passion of developing novel lipid therapies, especially a drug like obicetrapib. We're addressing a very large unmet medical need, 35 million-plus Americans and globally that need LDL-lowering despite usual standard of care, which is primarily statins. It's at least a $3 billion to $4 billion global market opportunity. And based on our multiple Phase II trials, we achieved a 43% mean LDL lowering as monotherapy and 59% mean in combination with ezetimibe, which is we're developing as a fixed-dose combination. We have excellent tolerability through our Phase II trials and now we have blinded data in over 10,000 patients, and we're seeing remarkably well-tolerated drug and no adverse safety signals to these very large Phase III trials to-date. We also have a robust effect on not just LDL but a number of other important lipid parameters, ApoB, non-HDL cholesterol, HDL cholesterol and Lp(a). It's an oral, once a day without regard to food or therapy and we just completed a secondary financing, and we have over $500 million in the bank, which will fund us throughout the next few years of Phase III clinical trials. So we had a very good year execution-wise. We completed our Phase III enrollments and we're ready to finish enrollment for our pivotal Phase III outcome study called PREVAIL. And we initiated just recently our Phase III fixed-dose combination with ezetimibe called the TANDEM trial. And over the next 12 months, we're going to have readouts from our pivotal LDL Phase III trials, BROOKLYN and BROADWAY in TANDEM in the first quarter of 2025 and then ultimately, our outcome study PREVAIL towards the end of 2026. We also have some exciting data on Alzheimer's disease, which we've released top line. This is an important kind of very important unmet medical need through the ApoE4, its a lipid gene, and we hope to share data from our BROADWAY trial regarding potential effects of biomarkers for Alzheimer's in that important LDL Phase III trial. The unmet need is quite substantial. We're talking about 30 million patients in the U.S. who are not at goal. And that's broken down into certain categories. 72 million Americans have hypercholesterolemia, high LDL levels, 43 million have primary prevention treatment, which is -- they don't yet have cardiovascular disease. And that goal should be less than 100 milligrams per deciliter. That represents over 18 million Americans that need further LD-lowering drugs on top of stats to achieve that less than 100 minimal target for those patients. We also have 19 million with established cardiovascular disease and very high risk in which the goal should be below 55 milligrams per deciliter above that level, recommended additional therapy is put forward by the guidelines. And therefore, represents 8 million Americans who have LDLs above 55 where something else should be added to a statin. And then 10 million who have not even had their LDL levels treated and high risk and everybody sensing another 5 million above 70 milligrams per deciliter. So we have a very, very large market. And what's exciting about it from a clinical perspective is we had a period of time where the guidelines were a little bit ambiguous about what to do to add to statins and now we have more and more consensus that we want to add to statins if necessary to get LDL levels down, certainly below 55 for these very high-risk patients. So here is where we are with the present targets. As I mentioned, below 100 is the primary engine target, 29% of those have achieved that target a lot more yet to get to goal 70 for that ASCVD with high risk and then only 10% of patients who have very high risk have LDLs below 55. So clearly, the unmet medical need is very great, and we have a drug, obicetrapib that can address this unmet medical need very effectively, and I'll show you the data on that in just a few minutes. I rarely do this before, but one of the big disappointments for me as a lipidologist, cardiologist was in 2013, the guidelines shifted away from goals. America had established for 20-plus years that we should achieve an LDL goal of below 70 for our high-risk patients. And due to multiple factors, but primarily due to the lack of evidence from the trials of adding to a statins achieving a benefit is galvanized or revised. And unfortunately, we can't necessarily say it cause an effect, but what we can say is once those guidelines were modified, heart disease rates have actually climbed significantly and LDL levels have plateaued and they're now starting to come down a little bit with more aggressive guideline recommendations. And what changed in the last 10 years has been more and more evidence from multiple trials, 2 PCSK9 trials, 1 CTP inhibitor trial and 1 ezetimibe trial and that one with bempedoic acid, showing that the more you lower LDL on top of statins, greater the cardiovascular. So lower is better is clearly back and that's going to have impact on a drug like obicetrapib, which can show very dramatic LDL-lowering effects in a well-tolerated oral therapy. And we've seen this change in the market. We've seen growth in statins, growing as a generic drug significantly with the more intense guidelines now being reestablished. Ezetimibe, which was languishing for many years, even though it was a $4 billion or $5 billion drug back in 2008, is now again growing significantly based on new guidelines and the branded drugs in general, including the injectable PCSK9 inhibitors, Repatha and others, we're seeing growth in all the branded drugs, again, with this new paradigm shifting back to more aggressive LDL lowering. And that brings us to obicetrapib and how it compares to the other options available or soon to be available in the next 3 years for patients. We really only have 2 oral options to add to statins; 1, generic ezetimibe, it lowers LDL, roughly 25%. it's safe, it's well tolerated. And as I mentioned, it's growing now significantly to add to statins. But for most patients, ezetimibe alone adding statins is not going to be adequate. Nexletol is branded. It has efficacy comparable to obicetrapib in that 15% to 20% range. It does have some side-effects that have been put in the label tendon rupture and gout warnings and so forth. It also has the added burden of requiring, in most cases, prior authorization. So consequently, with a drug that has a modest benefit on LDL lowering and not a clean safety profile, we haven't seen the uptick that we'd expect. But I think primarily it is due to the fact that we have a drug that doesn't really get to that treatment inertia threshold where doctors want to add another drug to get everyone therefore, to where they should be when it comes to the guidelines. The injectable drugs can do that. They can lower LDL in that 50% range. But there are injections that require training and even speaking from my own personal experience, I am a full-time nurse that I can do the training and do the prior authorizations for me in my lipid clinic. But most doctors just do not have those resources and consequently, most doctors shy away from using these drugs that are challenging to implement and especially in primary care practices. We have an oral PCSK9 on the market, pending in the market with Merck and starting Phase III. It lowers LDL about that 50% range. But the challenge, I think, for this oral therapy is, it has a very prominent food effect. You have to take it after 8 hours of fasting and now within 30 minutes of any other food or medication. And for most patients who are taking many other therapies in general, this could be a hurdle that will make it more challenging to utilize very broadly. So we have obicetrapib, I'll show you the data, lower LD on that 43% to 51% across multiple Phase II trials, oral, no food effect, well tolerated compared to placebo and also has the benefit of lowering Lp(a), a very exciting novel target with many studies underway looking at lowering Lp(a) through cardiovascular events. This is the most potent oral Lp(a) therapy to be available with our approval, hopefully, in the coming years. We also have a combination with ezetimibe, 2 very well-tolerated drugs, oral added together. We've already developed the fixed-dose combination with good bioavailability, using PK as the benchmarks for the combination treatment and we started our pivotal Phase III trial called TANDEM looking at both drugs together. In Phase II using 2 drugs that can commonly dosed together, we saw a 59% LS mean reduction, which achieved dramatic goal achievement in almost all patients who are already taking high-intensity statins. So here's the comparison across not just other lipid therapies, but across the other CETP inhibitors. This has been from the very beginning of NewAmsterdam, one of the key questions we had to address. What about the other failures in the class of CETP inhibitors. It's important to understand the historical context. These were drugs developed for HDL raising. At the time, HDL was considered the Holy Grail of risk reduction. Every 1% decrease in HDL is associated with a 3% increase in risk. So raising HDL was thought to be a very important way to ultimately reduce cardiovascular events. So these drugs are developed for that purpose in mind. They raised HDL somewhere between 40% to 75%, but their LDL lowering was actually quite modest, anacetrapib and evacetrapib in that 20% range and dalcetrapib, very little LDL lowering. They all went into outcome studies. And what's important is that anacetrapib actually worked. It was designed for HDL raising, so the baseline LDL was very low, but did in fact validate the LDL-lowering mechanism of CETP inhibition and resulted in an expected -- even a greater-than-expected cardiovascular benefit. Evacetrapib, again, developed for HDL raising and even though it had modest LDL-lowering effects, it went into an outcome study, which was quite short. We now know that 2 years is not long enough to see a benefit, and therefore, did not show a benefit. It was safe. It had actually a total mortality reduction that did not show a major adverse cardiac event reduction. Then dalcetrapib had really had no effect on LDL, again, very safe in 2 large outcome studies did not show a MACE benefit. So when we think about the other CT inhibitors, one of the biggest conclusions we can make is that the LDL lowering mechanism of those drugs do an effect result in a cardiovascular benefit. Then we have the injectable drugs, Repatha, Praluent and LEQVIO, Repatha and Praluent having outcome studies that were done at the time, again, very quickly, very large trials, trying to show a benefit. Again, in hindsight, it was done very quickly too, at the time because there was a concern the drugs would not be approved until Outcome studies were established. So they did these large Outcome studies, so a 15% relative risk reduction, again, as much as expected. But if they would have gone longer, and this is an important point that we've learned from, it would have gone longer,. In fact, if they just went -- drug for a year, the relative risk reduction going to go up from 15% up to 20%. And then LEQVIO is the RNAi approach that is also now underway with large cardiovascular outcome studies. So here's how we compare the LDL lowering of obicetrapib to other CETP inhibitors. And it's all based on design, the drug was designed for greater CETP inhibition. And that results in much greater LDL lowering. And especially when you look across the class, the more CETP is inhibited, the more results in lowering of LDL cholesterol as well as Lp(a) lowering an ApoB reduction. So obicetrapib is, by far, the most efficacious of the CETP inhibitor class. We know from genomic data, the more you have loss of function CETP, the greater the LDL lowering the greater the cardiovascular benefit. In fact, CETP for many years now has been known as longevity gene. If you have a loss of CETP activity, you have longevity present in the population. So we designed our program with that considerable benefit in mind and how do we maximize the opportunity to show this benefit in clinical trials. We have a drug that lowers LDL much more effectively through greater CETP inhibition. It has no effect on blood pressure, which was the big issue for torcetrapib. We know it does not affect aldosterone, which is, we believe, is the linkage between the blood pressure increase and the mortality increase with torcetrapib. we see none of that with obicetrapib as we didn't see any of that with the other CETP inhibitors as well, which were going to be very, very safe in their large Phase III trials. This is our LDL lower, it gets more effective. I mentioned our Lp(a) lowering is also much more effective, which we believe could translate into a greater uptick among clinicians who are looking for a drug that can lower Lp(a). When you think about what statins do, statins lower LDL, but they raise Lp(a), they raise the risk of diabetes, and they do not lower the small dense LDL particles. A drug like obicetrapib, we can lower the risk, lower the Lp(a) levels quite substantially, lower the risk of diabetes, which has been proven for all the drugs in this class as well as dramatically lower the small LDL particles. In our Phase II trials, we saw a 90% reduction in small particles, which is linked to greater cardiovascular risk. We designed our Outcome study to highlight these differences and what was learned from all the previous trials. So now we're focusing on LDL lowering. And to maximize the LDL-lowering effect, you want to have the highest baseline LDL feasible. So in our case, with PREVAIL, we have over 100 milligrams per deciliter LDL level, the REVEAL trial, which was the anacetrapib trial, had an LDL baseline of 61 milligrams per deciliter. So we expect, therefore, to have with greater LDL lowering efficacy in a much higher baseline, a much greater absolute LDL lowering, which we know is what correlates with clinical benefit. Every one millimole or 40 milligram per deciliter drop in LDL, absolute LDL lowers risk by about 22%. And so we believe with our design of PREVAIL, we can maximize this absolute LDL lowering, and therefore, achieve a greater relative risk reduction. The other big issue is follow-up. We've learned from all the other trials that going too short can minimize the benefit and the longer you can go in a trial, see the benefit, the greater the relative risk reduction. So here's the experience from REVEAL, that it was 30,000 patients again, the median baseline LDL was 61. But in the 10,000 patients who had the higher LDL or using non-HDL here is what was reported in the paper, there was a 21% relative risk reduction with a 21% LDL lowering in that 23 milligram per deciliter drop in non-HDL cholesterol resulted in a 17% relative risk reduction. That's exactly what -- as expected effect. It's actually better than expected based on that formula I shared with you. So 23 milligrams per deciliter is if 40 milligrams per deciliter is associated with a 22% drop, 23 milligram per deciliter drop would be less than 17%. And just to be comparable, the bempedoic acid trial, clear outcomes had a very similar relative risk reduction, absolute LDL lowering of 22 milligrams per deciliter had a 13% relative risk reduction. So this 17% is actually as good, if not better than expected. So for us, in our clinical trial, we have a much higher baseline LDL non-HDL cholesterol of 140, expected around a 40% non-HDL cholesterol lowering. Therefore, 56 milligrams per deciliter is our estimated absolute non-HDL lowering should translate to at least a 20% relative risk reduction. So not only a better drug, but a better clinical trial program. We want to make sure that our outcome study does not fail the drug. And that's our premise behind designing a trial. And to do that, we've obviously got a much better LDL drug, but we also have a minimum follow-up of at least 2.5 years. This is the longest minimum follow-up of any outcome study of recent history when it comes to duration of follow-up for the last patient enrolled in the trial. As I mentioned already, the PCSK9 inhibitor trials were 15%. If there are other drugs released 1 year that 15% went for 20% relative risk reduction. So here's our pool data across all of our Phase II trials showing that average of 42.6 LS mean LD lowering. This almost always translates into Phase III efficacy of a similar magnitude. As I mentioned, we've been very pleased with our performance, our execution of all these trials. We're a very experienced team on conducting clinical trials. That's my background as well as our Co-Founder, John Kastelein and our team that's involved with us and operations. We enrolled the BROADWAY and BROOKLYN trial, either on schedule or ahead of schedule. The readouts will happen relatively soon. BROOKLYN will be in the third quarter, BROADWAY in the fourth quarter of this year. BROOKLYN is a trial with Familial Hypercholesterolemia, 350 patients, 2:1 randomization. BROADWAY is those with primarily Atherosclerotic cardiovascular disease, both studies are on maximum tolerated statins. And that study will read out in the fourth quarter 2025, the BROOKLYN trials 2,500 patients and it will be both LDL is the primary endpoint as well as safety. And I think, again, one of the key strategies that we started with the company is the start of outcome study as soon as possible, knowing that outcomes are going to be very important. And we've also learned from experience from other drugs that have been launched, we want to have outcome data in hand when we launched the drug. And so we started our PREVAIL outcome study at the same time as our LDL-lowering trials to give us the readout as soon as possible after the completion of the LDL studies and we expect to have that study completed with [indiscernible] follow-up with our last patient being enrolled relatively soon. Fast-forward 2.5 years, we finished the treatment period of the trial, so we should have the readout towards the end of 2026. And then we have our fixed-dose combination, which is the TANDEM study that started enrollment. It should go relatively quickly. That should read-out in the first quarter of 2025. As I mentioned, we do have an Alzheimer's program looking at cholesterol metabolism of the brain, which is potentially benefited by obicetrapib. We have a good science behind that as well as genomic validation and animal data supporting the concept there for ApoE4 high-risk patients for Alzheimer's disease. So here's the BROOKLYN trial in more detail, 2:1 randomization. That will be our first Phase III trial readout in the third quarter. And then we have the BROADWAY trial, as I mentioned, 2:1 as well, 1,600 patients on active 800 of placebo, we over-enrolled that trial. So actually 2,500 patients overall for that important both efficacy and safety on for obicetrapib in that high-risk population. And then PREVAIL, I mentioned, we want to make sure that the study does not fail the drug. And this is where we've learned a lot from all the previous trials. It's not about the size of the trial, it's important, it's about the duration. We do have 9,000 patients that have high risk for cardiovascular -- who is already having preexisting cardiovascular with LDLs of 55, 4-point MACE is our primary endpoint. And we also look at some of the other important parameters that have been associated with this class, such as the prevention of pre-diabetes conversion in diabetes and also A1c reduction with this therapy, which has again been shown for all the other previous CETP behaviors. We have a very well treated population. Many of them are on other therapies like GLP-1s, which again, for us, seeing the benefits of that, the SELECT trial, the LD levels aren't changed by GLP-1 therapy. Risk does go down, but LDLs still remain high. So we do think that that's going to be important to add to GLP-1 therapy for those high LDL patients that still need for the cardiovascular risk reduction. A very effective drug that lowers LDL, a much higher baseline LDL, longer duration of follow-up that also to further enhance the benefits of obicetrapib, we selected patients we know from the REVEAL trial had greater benefit with a CETP inhibitor. Those include those with high triglycerides, low HDL, high LPLA. And so we enriched our trial with those high-risk patients that we believe could result potentially in greater amount of risk reduction. And I mentioned we have these differentiated secondary endpoints like Lp(a) lowering and HDL raising Alzheimer's disease, which are going to be a very exciting upside opportunity for this drug if it can share those benefits in these very large outcome studies. So here's our summary. We've executed very well operationally enrolling our trials either on schedule or ahead of schedule or over-enrolling these trials. As I mentioned, we have a very, very good Phase II data across the range of 6 different studies, showing very robust efficacy and great tolerability and that was 2023. And now 2024 is a very, very important year for us with 2 large Phase III lipid trials reading out over the next 6 months. And then our fixed dose combination of follow in the first quarter of 2025 and then finishing enrollment for PREVAIL this quarter. And then ultimately, 2.5 years later, roughly have the results of that trial. And then we have a great commercial team in place. BJ Jones, our Chief Commercial Officer, led the launch of Nurtec for Biohaven very successfully. So we're planning on gearing up for that over the next 2 years. And again, most importantly, we're going to have outcome data in hand when we launched the drug to maximize both the uptake among -- with payers and with the IRA, so forth, maximizing the launch trajectory to get the greatest value for this drug for both patients and for investors. So thank you very much, and I'm very pleased to take any questions you might have. Yes.

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Yes, it's a good question. I think it's still robustly lower as ApoB. Our AOB lowering is 30%, LDL lowering in the 40% range. So it's still a very effective ApoB lowering, right? It was also very important for the key opinion leaders to get excited about obicetrapib was the better ApoB-lowering, the other CDM here is more like 15%. Now one of the things we discovered -- and it's now documenting the literature is that we lower LDL particles by 50% overall, even greater than expected than ApoB or LD because the LDL lowering is 40% plus LDL particle lowering 50%, but lower is the small particles by 90% plus. Now it turns out small particles have less ApoB mass per particle. And so when you lower predominantly small particles, you are going to get a little bit less ApoB lowering because every particle has 1 ApoB, but for the small particles, there's less ApoB mass there. So ApoB being a mass assay, we see ApoB lowering not quite as robust as you would expect for the LDL particle reduction. The thing is when you look at the data about LDL particles versus ApoB, actually, ApoB underperforms LDL particles when it comes to outcome benefits. And then two head-to-head trials, LDL particle has actually outperformed ApoB for showing a benefit. So we think our very effective LDL particle lowering of 50% and especially the small part was going down by 90%, we believe that's going to translate into very substantial cardiovascular risk reduction Okay. Any other questions? We'd be happy to -- we'll hang around too if you want to ask any questions. So thank you very much for coming. Appreciate it.