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, the audience has our CFO, Ian Somaiya, and our head of IR, Matt Phillips. Here's our disclaimers. So I wanna give you a brief overview about NewAmsterdam Pharma. Just a bit way of background for myself, I'm a cardiologist, lipidologist, been starting biotech companies for the past 15 years.
I also still see patients three or four days a month at the University of Chicago, run the lipid clinic there. So for me, this is a real passion, developing novel lipid therapies, especially a drug like obicetrapib. We're addressing a very large unmet medical need, you know, 35 million-plus Americans, well, and globally that need LDL-lowering despite the usual standard care, which is primarily statins. It's at least a $3-$4 billion global market opportunity.
Based on our multiple phase II trials, we achieve 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 a remarkably well-tolerated drug and, and no adverse safety signals through 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, oral therapy. And we just completed a secondary financing, and we have over $500 million in the bank, which will fund us, you know, 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. We initiated just recently our phase III fixed-dose combination with ezetimibe called the TANDEM trial. Over the next 12 months, we're gonna 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, which is 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, 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, you know, further LDL-lowering drugs on top of statins 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 that represents eight 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 that represents another five 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 the statins, and now we have more and more consensus that we wanna add the statins if necessary to get LDL levels down, certainly below 55 for these very high-risk patients.
H ere's where we are with the present targets. As I mentioned, below 100 is the primary intervention target. You know, 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.
C learly, the unmet medical need is very great, and we have a drug, obicetrapib, that can address this unmet medical need, you know, very effectively. And I'll show you the data on that in just a few minutes. I alluded to this before, but one of the big disappointments for me, as a lipidologist, cardiologist, was in 2013, the guidelines shifted away from goals. The American Heart had established, you know, for 20-plus years that we should achieve an LDL goal 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 statin, achieving a benefit, these guidelines were revised.
U nfortunately, we can't necessarily say cause and 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, you know, with more aggressive guideline recommendations.
W hat changed in the last 10 years has been more and more evidence from multiple trials, two PCSK9 trials, one CETP inhibitor trial, and one ezetimibe trial, and now one with bempedoic acid, showing that the more you lower LDL on top of statins, the greater the cardiovascular risk. So lower is better is clearly back, and that's gonna 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 $4-$5 billion drug back in 2008, is now again growing significantly based on, on new guidelines.
The branded drugs in general, including the, injectable PCSK9 inhibitors or Repatha and, and others, we're seeing growth in all the branded drugs, you know, again with this new paradigm shifting back to, you know, more aggressive LDL-lowering. That brings us to obicetrapib and how it compares to the other options available or soon to be available or in the next few years for patients. We really only have two oral options to add to statins. One, generic ezetimibe, you know, lowers LDL roughly 25%.
That's, 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 to statins is not gonna be adequate. Next to the tolerability of branded, it has efficacy comparable to ezetimibe in that 15%-20% range. It does have some side effects that have been put on the label like tendon rupture and gout warnings and so forth. And it also has the added burden of requiring, in most cases, prior authorization. So consequently, with a drug that has modest benefit on LDL-lowering and not a squeaky clean safety profile, we haven't seen the uptake that we'd expect.
I think primarily it's through the fact that we have a drug that doesn't really get to that treatment inertia threshold where doctors wanna 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 they are injections, they require training. And even speaking from my own personal experience, I have a full-time nurse that I can do the training and do the prior authorizations for me in my lipid clinic, but for most doctors just do not have those resources. And consequently, most doctors shy away from using these drugs that are challenging to implement in, especially in primary care practices.
We have an oral PCSK9 on the market, and coming pending in the market with Merck and starting phase 3. It lowers LDL by 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 not within 30 minutes of any other food or medication. And so 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, and I'll show you the data. Lowers LDL in that 43%-51% across multiple phase 2 trials. Oral, no food effect, well-tolerated compared to placebo.
It also has the benefit of lowering Lp(a), a very exciting novel target, with many studies underway looking at lowering Lp(a) to reduce cardiovascular events. This is the most potent oral Lp(a)-lowering therapy to be available, with our approval, hopefully, in the coming years. We also have a combination with ezetimibe, two very well-tolerated drugs, oral added together.
We've already developed the fixed-dose combination with good bioavailability, using, you know, PK as the benchmarks for the combination treatment. We started our pivotal phase III trial called TANDEM looking at both drugs together. In phase II, using two drugs, concomitantly 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.
H ere's the comparison across not just other lipid therapies, but across the other CETP inhibitors. This has been, you know, from the very beginning of NewAmsterdam, one of the key questions we had to address. You know, 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, the holy grail of risk reduction.
Every 1% decrease in HDL was 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 were developed for that purpose in mind. They raised HDL somewhere between, you know, 40%-75%, but their LDL-lowering was actually quite modest. The 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 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 two 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. It did not show a major adverse cardiac event reduction. Then dalcetrapib had really no effect on LDL. Again, very safe in two large outcome studies. It did not show a MACE benefit.
W hen you think about the other CETP inhibitors, one of the biggest conclusions we can make is that the LDL-lowering mechanism of those drugs do in fact 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 to at the time because there was concern the drugs would not be approved until the outcome studies were established. So they did these large outcome studies, saw 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, they would have gone longer.
In fact, if they just went at least a drug for a year, the relative risk reduction would have gone 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 obecetrapib to other CETP inhibitors. And it's all based on, you know, design the drug was designed for greater CETP inhibition, and that results in much greater LDL-lowering.
E specially when you look across the class, the more CETP is inhibited, the more it results in a lowering of LDL cholesterol as well as Lp(a)-lowering and ApoB reduction. So obecetrapib 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.
I n fact, CETP for many years now has been known as a longevity gene. If you have 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 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, we didn't see any of that with the other CETP inhibitors as well, which were known to be very, very safe in their large phase III trials.
Just as our LDL-lowering is 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, you know, 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, we 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 wanna 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.
W e expect therefore to have with greater LDL-lowering efficacy and a much higher baseline, a much greater absolute LDL-lowering, which we know is what correlates with clinical benefit. Every 1 millimole or 40 milligram per deciliter drop in LDL, absolute LDL, lowers risk by about 22%. And so we believe, you know, 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. The longer you can go in a trial to see the benefit, the greater the relative risk reduction. So here's the experience from REVEAL. That was 30,000 patients. Again, the median baseline LDL was 61. But in the 10,000 patients who had the higher LDL, we're using non-HDL here is what was reported in the paper. There was a 21% relative risk reduction with a 23% LDL-lowering. And that 23 milligram per deciliter drop in non-HDL cholesterol resulted in a 17% relative risk reduction. And that's exactly what is expected. In fact, it's actually better than expected, you know, based on that formula I shared with you.
So 23 mg/dL is, if 22 mg/dL is associated—sorry, 40 mg/dL associated with a 22% drop—23 mg/dL 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 mg/dL 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 mg/dL 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 and that's our premise behind designing a trial. To do that, we've obviously got a much better LDL-lowering drug, but we also have a minimum follow-up of at least two and a half 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 they were on the drug for at least one year, that 15% went to 20% relative risk reduction. Here's our pooled data across all of our phase II trials, showing that average of 42.6 LS-mean LDL-lowering. This almost always translates into phase III efficacy of a similar magnitude.
As I mentioned, we've been very, 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 on operations. We enrolled the BROADWAY and BROOKLYN trials 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-to-1 randomization. BROADWAY is those with primarily atherosclerotic cardiovascular disease. All both studies are on maximum tolerated statins, and those studies will read out in the fourth quarter 2025. The BROADWAY trial is 2,500 patients. And it'll be both LDL is the primary endpoint as well as safety.
I think, again, one of the key strategies that we started with, with the company was to start our outcome study as soon as possible, knowing that, outcomes were gonna be very important. We've also learned from experience from other LDL trial other drugs that have been launched. We wanna have outcome data in hand when we launch the drug.
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. We expect to have that study completed with 2.5-year minimum follow-up with our last patient being enrolled relatively soon. Fast forward 2.5 years we finish the treatment period of the trial. So we should have the readout towards the end of 2026.
Then we have our fixed-dose combination, which is the TANDEM study to start it in 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 in the brain, which is, potentially benefited by obicetrapib.
We have a good, 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-to-1 randomization. That'll be our first phase III trial readout in the third quarter. And then we have the BROADWAY trial, as I mentioned, 2-to-1 as well, 1,600 patients on active, 800 on placebo. We over-enrolled that trial.
So it's actually gonna be 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 wanna 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 that's important. It's about the duration.
We do have 9,000 patients, that have high risk for cardiovascular disease, already having preexisting cardiovascular disease with LDLs above 55. 4-point MACEs are our primary endpoint. And we also gonna look at some of the other important, parameters that have been associated with this class, such as the prevention of prediabetes conversion and diabetes, and also A1c reduction, with this therapy, which has, again, been shown for all the other previous CETP inhibitors. 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 LDL levels aren't changed by GLP-1 therapy. Risk does go down, but LDL levels still remain high. So we do think that that's gonna be important to add to GLP-1 therapy for those high LDL patients that still need further cardiovascular risk reduction.
But with a very effective drug that lowers LDL, a much higher baseline LDL, longer duration of follow-up, but also to further enhance the benefits of obicetrapib, we selected patients that we know from the REVEAL trial had greater benefit with a CETP inhibitor. Those include those with high triglycerides, low HDL, high Lp(a). And so we enriched our trial with those high-risk patients that we believe could result potentially in greater relative risk reduction.
I mentioned we have these differentiated secondary endpoints like Lp(a) lowering and HDL raising, Alzheimer's disease, which are gonna 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 ahead, either on schedule or ahead of schedule or over-enrolling the trials.
As I mentioned, we have very, very good phase II data across the range of six 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 two large phase III lipid trials reading out over the next six months. And then our fixed-dose combination to follow in the first quarter of 2025.
And then finishing enrollment for PREVAIL this quarter, and then ultimately 2.5 years later, you roughly have results of that trial. And then we have a great commercial team in place, BJ Jones, Chief Commercial Officer, led the launch of Nurtec for Biohaven very successfully.
So we're planning on gearing up for that over the next two years. And again, most importantly, we're gonna have outcome data in hand when we launch 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. So I think I was reading about this.
There were some discussions about other mechanisms we've seen in turnover reduction of LDL and ApoB. With CETP inhibitors, the ApoB reduction seems to be a little bit lower. How do you look at that and to that pain point?
Yes. That's a good question. I think it's still robustly lower as ApoB. Now, our ApoB lowering is 30%, LDL lowering in the 40% range. So it's still a very effective ApoB lowering drug. That was also very important for the key opinion leaders to get excited about obicetrapib was the better ApoB lowering that the other CETP inhibitor was more like 15%.
Now, one of the things we discovered, and it's now documented in the literature, is that we lower LDL particles by 50% overall, even greater than expected than ApoB or LDL 'cause LDL lowering's 40%+ LDL particle lowering 50%. But it lowers the small particles by 90%+. Now, it turns out small particles have less ApoB mass per particle.
And so when you lower predominantly small particles, you are gonna get a little bit less ApoB lowering 'cause every particle has one 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.
Now, 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 in two-head-to-head trials, LDL particles actually outperformed ApoB for showing a benefit. So we think our very effective LDL particle lowering of 50%, and especially the small particles going down by 90%, we believe that's gonna translate into very substantial cardiovascular risk reduction. Okay. Any other questions?
We'd be happy. We'll hang around too if you wanna ask any questions. So thank you very much for coming. Appreciate it.