Okay. Yeah.
All right. Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference. For our next session, very excited to be hosting NewAmsterdam Pharma. We have a hybrid presentation and fireside-style chat Q&A. It's my pleasure to introduce Dr. Michael Davidson, NewAmsterdam Pharma CEO and Co-founder, and also Ian Somaiya, the Chief Financial Officer. With that, thank you very much for joining us. I'll hand it over to you, Michael, to get the presentation started.
Thanks, Tyler, and thank all of you for joining me this morning. We've had a very productive, exciting, you know, past 18 months. Completed our pivotal Phase III trials, BROOKLYN, TANDEM, and then BROADWAY, demonstrating an exceptionally well-tolerated drug profile, LDL efficacy, and of course, the demonstration of a 21% MACE benefit with BROADWAY at the end of our, you know, Phase III program and showing how pooling all that data together resulted in a significant reduction in MACE throughout our Phase III program. To get ready for commercialization of the drug, we've a world-class Medical Science Liaison developed, going out and seeing KOLs across the United States. We've now doubled in size, over 100 people throughout the world, largest number in our commercial office outside of Pennsylvania.
Of course, following the BROADWAY data, we secured another financing, we hopefully have $730 million as end of year 2025. We've published this data, if you're gonna look at the literature, we're fully proud of the fact that we've published The New England Journal of Medicine, you know, The Lancet, Nature, very high-profile journals, you know, published our Phase III program. The unmet need is incredibly big and getting bigger. We say 30 million, with latest data from VESALIU.S.-CV in particular, this outcome trial with Repatha, it's now getting to be a much bigger population at need based on the evidence. That trial showed that in the population not yet having heart attack or stroke, that getting LDL levels below 55 resulted in a total mortality benefit.
That increased the size of the market even more so than I describe here. What it also means is that 55 becomes the new goal, which is what's expected based on the data. That means more and more people, roughly 90%, will not get to that below 55 target with statin therapy alone, so the unmet need for combination therapy is growing dramatically, you know, based on the latest evidence. What we have with obicetrapib is something incredibly differentiated from any other LDL-lowering therapy. Of course, it lowers LDL very well, alone and in combination with our fixed-dose combination with ezetimibe. We're approaching or comparable to the LDL reductions you get with injectable therapies. Also, what is important about obicetrapib is it's very differentiated from any other LDL-lowering therapy. It provides benefits across the spectrum of lipid risk.
It raises HDL, of course. That's one of the, you know, the highlights of the drug, a 150% increase in HDL. We showed from BROADWAY data using p-tau217, an exceptionally good biomarker of amyloid in the brain, reductions of amyloid deposition over 12 months in the APOE4 homozygotes in particular, which represents a very significant increased risk of Alzheimer's disease. Roughly 25% of patients with Alzheimer's have either 3, 4 or 4. Sorry. 45% of the population have either 4 or 3, 4, represents over two-thirds of Alzheimer's disease. The LDL particle reduction is a highlight, lowering small particles by 90%.
One of the key differentiators, which I know many of you are focused on, is the reduction of Lp(a), which is 50% in that 50 to 150 range, which is important because that's the target population in which the injectable drugs will not be available. I just... on my lipid clinic last week, I saw roughly 40 patients. Out of those 40 patients, 38 had high Lp(a). Now, those 38, actually very few are gonna qualify for the injectable therapies because they, Lp(a) levels are not either high enough or they don't yet have existing heart disease, which is gonna be the criteria for these injectable therapies when they're available.
Also, unique across the class, it's been demonstrated, you know, five times already, including our own BROADWAY data, that CETP inhibition reduces the development and progression of diabetes, unlike statins, which increase the risk of diabetes. Here's our differentiations in more detail, but this is the key for our, what we believe is gonna be the success of obicetrapib commercially. It lowers LDL in a, with an oral very well-tolerated medication, and it has these other benefits that drive utilization. These are highly motivated factors. Prevention of Alzheimer's, we hope. We're gonna do more studies to validate this. Lowering Lp(a) and, of course, reduction of the diabetes, these are highly motivating factors for moving to obicetrapib versus any other LDL-lowering agent.
The key takeaways, recently, of course, that I highlighted already is that the lipid market is growing now substantially, especially the branded market, based on the fact that we're getting more aggressive targets to get to goal, and the guidelines are gonna shift accordingly. We've seen major growth in generic ezetimibe, for example, but also the branded drugs are growing quite rapidly, and we see that happening. That trend is really in gonna be important for us when we launch obicetrapib in the coming year or so. Here's just an example of that, the lipid market's growing, both the generic and non-statin, even statins are growing. Then branded, you can see how rapidly the branded drugs are growing over the last few years.
This is going to accelerate, again, based on the new data and the entry in the market of oral Enlicitide, which is the Merck oral PCSK9. It's really important to highlight that getting the goal below 55 on statins alone is not achievable for about 90% of patients. That's going to be our target population when it comes to when we launch obicetrapib for lowering LDL therapy with our MACE benefit in the public domain. Here's our comparative data across all our trials, a very consistent benefit on LDL lowering with the monotherapy. Obicetrapib plus ezetimibe gets us to the same LDL levels that we see with the injectable Repatha, for example, and even the oral PCSK9 inhibitors. We're going to be right in line with that with our fixed-dose combination with ezetimibe.
Here's our goal achievement with TANDEM, which is our fixed-dose combination, 90% approximately get the goal, over 70% get the goal below 55 in combination with high-intensity statins. What's exciting, of course, was the demonstration in the BROADWAY trial of a 0.79 hazard ratio. What was key about this was the biological processes is very in line with what we saw in our data, that it takes time for the plaque to stabilize and therefore prevent events. We see at that six-month mark, we see the reduction of events occurring, and the overall reduction was 0.79. In the first six months, they're flat. Then in the second six months, we got this 40%, 34% reduction.
If you pulled our data in Phase II, Phase III altogether and looked at the same analysis and looking at the 3-point MACE that was used in the REVEAL trial, which is non-fatal MI, CHD death, and revascularization, we did achieve statistical significance. That was published in the Journal of American College of Cardiology. The question is why? Why do we see this greater than expected benefit at just one year? You roughly expect about half your benefit from LDL lowering in the first year compared to subsequent years. Once you hit after the first year, you get your full benefit. In the first year, it's about half the benefit. We saw 21%. When you model this, you can explain the LDL lowering benefit is roughly 9%. Then we did some modeling on what would help determine this benefit.
We believe it's the LDL particle reduction, especially the small particles of 90%, and the Lp(a) lowering, which should translate to about a 5% overall benefit. When you look at this modeling, that comes out to 21%. Of course, the ultimate test will be the PREVAIL trial to show this benefit in a much larger trial over a longer duration of treatment. Of course, I mentioned the diabetes benefit. This is a key differentiator. We saw that statistically significant difference in new onset diabetes mellitus or worsening glycemic control. We also saw trends in the right direction for renal improvement with obicetrapib, which is quite exciting. We believe this is driven by the HDL raising benefit, not the LDL lowering, because we don't see LDL lowering across the board, if anything, worsens diabetes risk for both statins and PCSK9 inhibitors.
The HDL raising effect is what's responsible for the protection from development of diabetes with obicetrapib. Of course, everyone's anticipating the PREVAIL trial. We have purposely designed our Phase III program with BROADWAY to match what PREVAIL could ultimately do. The 21% we saw at one year was a very similar patient population, both on LDL and cardiovascular risk. We had the same steering committee, the same adjudication committee, basically many of the same sites as PREVAIL. BROADWAY in many ways is a good test for what PREVAIL should accomplish. You can see how similar they are. If anything, PREVAIL would have a higher LDL, a little bit higher event rate than BROADWAY. Yet what we're saying is that we see this consistent at the first year mark.
We presented publicly that at the first year, we see the same overall blended event rate with PREVAIL versus BROADWAY. We feel, again, higher confidence in success of PREVAIL as we designed it. We wanted to maximize the LDL absolute reduction. That's been kind of the Achilles heel of other trials in the past. They start off with really low LDL baselines and the LDL lowering absolute benefit was modest. We wanted to maximize that. We have a higher absolute LDL because our baseline is roughly 100. We wanted to make sure the durability was great to achieve the benefit. That's also been one of the weaknesses of other trials going too short. You lose that benefit because you have to dilute the effect in the first year where you don't see much benefit.
This is the two and a half year minimum follow-up will happen at the end of this year, basically. It's still, just keep in mind, it's still event-driven and we're monitoring the blended event rates. We have, again, said publicly that we will update the investor community in roughly the mid-year mark for where we are with our blinded event rates and prediction of when actually we'll hit the event rates pre-specified for completing the trial. The two and a half year mark will be at the end of 2026. Lastly, I have a few more minutes 'cause it's one of my key excitement about the drug. When I started the company, I wanted to focus as well on Alzheimer's disease because of a number of important insights about HDL and Alzheimer's disease. Alzheimer's disease is now being redefined.
It's no longer just dementia and Alzheimer's are kinda synonymous, but now realize that Alzheimer's disease starts about 20 years before you get any symptomatology, any cognitive impairment. It's now a biological process, not just saying you have Alzheimer's and dementia or saying the same thing. With that in mind, you know, we recognize that APOE4, which is a lipid gene, is your biggest genetic factor for predicting Alzheimer's disease. And we believe that based on the data that APOE4 is impairing the ability of the brain to clear cholesterol properly. That's what HDL does. HDL is your lipoprotein that clears cholesterol from tissues.
Having the ability to raise HDL and affect cholesterol clearance, we believe will translate into clinical benefit in preventing Alzheimer's disease, which is a process that begins 20 years earlier than the cognitive impairment symptoms. We showed this in our BROADWAY data that if you had APOE4 for homozygotes, we saw p-tau217, a very good biomarker for amyloid, reductions comparable to the anti-amyloid therapies. Across the board, we saw in the full analysis set statistically significant benefits. Of course, all the APOE4 carriers, even greater benefits, in that 1-year trial. It was a relatively short study, so we weren't even sure what we would see, but we did see the statistical benefit, especially in the APOE4 and even more so in APOE4 homozygote patients, which represent, again, a 10-fold increased risk of Alzheimer's disease.
What's also important is you look at one biomarker, p-tau217, which is extremely good. I think that's where the future of Alzheimer's is going. We can see it. The publications on p-tau217 are going up exponentially as replacing PET, getting earlier diagnosis. Across the board, all the biomarkers improved. Neurofilament light, GFAP, it's a glial cell, fibrotic protein, another marker of progression, p-tau181 and Aβ42/40. All these things got better with obicetrapib , which again is consistent with the validation that this is a true benefit across that very high-risk population. Our plans are to do another trial, and we'll talk about that more in the coming days. I lost my computer, forward here, but I think I'll close out. Done with my 15 minutes anyway.
Just again, we're very excited about what we've accomplished. This year is a big year for us. A lot of different catalysts are gonna happen this year. Some externally, Lp(a) lowering, you know, being hopefully validated with the trial, there are many others to follow. We again finish our 2.5-year follow-up time period this year for PREVAIL, we'll continue to update the investor community and all of you know, with our progress with that trial and when we're gonna get more confirmation of when that trial is gonna actually complete for showing the benefits of PREVAIL. We are launching, Sorry, we're getting commercial approval in Europe and launching in Europe this year. The end of this year will be our approval at the EMA.
Again, we're looking forward to working with our partner, Menarini, on the launch of drug in certain European territories. Thank you, and we look forward to hearing your questions.
Wonderful. Thank you very much for that great presentation, Michael. You mentioned focusing on PREVAIL for a little bit. You mentioned that BROADWAY is a good test of PREVAIL. You're tracking the events. Two and a half years will be towards the end of the year. You'll let us know midyear whether it's gonna be end of the year or early next year. The 21% MACE benefit in BROADWAY at 12 months. My understanding with outcomes trials is that you get about half the benefit in the first 12 months. We just multiply that by 2 to get to 42%.
Yeah.
Right?
Yeah.
On the panel yesterday, a doctor was very excited about obicetrapib . He thinks you guys could put up 25%.
Right.
Not that we should be setting this expectation, but, what do you think is the minimum bar that PREVAIL needs to put up in terms of MACE benefit to see broad uptake in the KOL community versus PCSK9s? Do you think
Right
15% + or?
Right. I mean, I think We've done a lot of research on this with physicians and, what's important to point out, it really just, it's a positive trial that leads to labeling of the MACE benefit because, you know, the benchmarks have been 15% with Repatha, 15% with Praluent, 13% with bempedoic acid. They've all been highly praised for being positive trials. That's the benchmark that we're up against. Now, we believe we'll be better than that, but we don't need to be to be commercially successful. You know, we're trying to, you know, manage expectations here because, you know, we feel we have a great drug and it's well-differentiated.
Having a positive trial with Lp(a) lowering, you know, prevention of diabetes, prevention of Alzheimer's, you can see you don't need more than, you know, that plus a positive trial to get extremely good uptake among clinicians with a, with an oral therapy that lowers LDL very robustly, you know, more than any other. It will be comparable to the other oral PCSK9 therapies, if not better.
Yep. Fair enough. on the Lp(a) front, the Phase III Lp(a)HORIZON trial pelacarsen delayed again to the second half of this year. What are your and KOLs thoughts and, especially since you're, you know, as such a figure in the space, what are you hearing about that delay? What do you think it means for the outcome of the trial? Ultimately, from a NewAmsterdam Pharma obicetrapib perspective, what do you guys need to see to confirm the thesis that it's contributing to the MACE benefit?
Right. Well, I mean, of course, a positive trial would be great for us 'cause it validates the Lp(a) lowering on a... I'm confident we will see that ultimately. Is this the right trial to do that? I think it's that the jury is still out on whether it's the right trial, the right platform, you know, I think for lowering Lp(a) because what they had to do, which is the nature of these studies, they had to have a high enough Lp(a) to drive risk, but the LDL ended up being, you know, very low, 60. When you have a setting of very low LDL, that's how we treat Lp(a) today.
'Cause I think the argument with the patient is if a smart patient will say, "Why are you putting me on a statin? It raises Lp(a). Why do I wanna raise my Lp(a)?" Says, "Well, if you lower the LDL really low, it still mitigates the risk quite a bit." We don't know how much it mitigates the risk, and that's the question that we're gonna find from Lp(a)HORIZON. Also the platform itself, giving an injection at once a month, you know, I have some concerns about, you know, what that does from a physiological perspective, 'cause it is an inflammatory shot every month, which is... Again, inflammation is my other area with Corvidia and so forth, you know, how that could translate or impair the benefits of the Lp(a) lowering.
The other ones are OceanA is coming. It's an RNAi approach. Lilly has another one that's less, obviously even less frequently dosed. Orals are coming. I mean, the Lp(a)HORIZON's not gonna be the ultimate answer about how beneficially you can lower risk with Lp(a). That said, I mean, we have a couple scenarios where if it works out right, that's fantastic. If it works, and it has modest benefit, but there's also a lot of dropouts 'cause of skin reactions or other side effects, the benefit is not overwhelming. It still helps us a lot. That validates the Lp(a) lowering benefit.
If it doesn't work, or even it works modestly but not adequately to get approval, you know, we become the first Lp(a)-lowering drug on the market when we launch obicetrapib. Like I said, most people that are gonna qualify for an injectable drug, Sorry, most people that would not qualify for an injectable unless they have above 150 to 200 nanomoles per liter and they already have existing heart disease. Most people with high Lp(a) don't have that. We're gonna be the go-to therapy for those patients.
I saw some people in the audience perk up when you mentioned the inflammation and the once-a-month dosing.
Yeah.
Maybe you could just briefly elaborate on your thoughts there.
I don't know about the GalNAc. I hope it's a lot less, but when I was involved with Mipomersen, which is another ASO platform, and one of the concerns about that therapy was you got a big CRP spike every time you took a shot, and that was the mipo- It was ApoB antisense. We know that in the Lp(a) patient, having high CRP makes risk worse. That's a known fact. Again, I don't know what the GalNAc effects are. Hopefully they're minimal. I mean, they're minimal. It's a lot lower dose, so maybe that's not even a factor to consider. Like I said, if you had to think about what could go wrong with Horizon, that's one of the things you would think about.
I mean, the LDL's too low. The platform is not the right platform to lower Lp(a). Those are things that could go wrong. I'm convinced and I'm highly confident that ultimately we're having an Lp(a) drug that's gonna work, that's gonna show a benefit. Again, is it gonna be pelacarsen? I can't be 100% sure. I hope it is, but we will have to wait and see what the data tells us.
That's helpful. Yeah.
Then again, you know, Novartis went ahead and got another. They're everyone's banking on future, you know, future drugs in this, in this marketplace to really build upon, but hopefully HORIZON tells us.
Understood. You know, the third leg of the triple MOA of obicetrapib, small particles, 90% small particle reduction, I think, you know, people are not super convicted there relative to obviously LDL or Lp(a). What about the literature or your knowledge of small particles gives you conviction that it's contributing to the MACE benefit?
I think what's important to point out for small particles, these are known for many years that small particles are when they're elevated, the risk is so much higher. Small particles are made from CETP. CETP transfers triglyceride into LDL, in exchange for triglyceride. Triglyceride are transferred in LDL in exchange for cholesterol mass. The small LDL becomes smaller and gets hydrolyzed to smaller particles, which are more likely to penetrate the endothelium. It's a clearly a risk marker, and we think total particles themselves are very important so that when you look at total particle reduction, we're in that 50% range with overall, but 90% with the small particles. If you look at the epidemiology, they're very powerful risk factors for heart disease, the small particles.
We see that as a, as a positive benefit. PREVAIL will be the ultimate answer about that because we'll see what the benefits are. If it outperforms what you'd expect, that would be another good explanation for that.
We can also go back to the REVEAL dataset.
Right.
Looking at the highest quartile. There, the 23 mg per deciliter drop in LDL that was seen translated to a 17% MACE benefit. The same LDL drop that was reported by bempedoic acid in their trials, which equated to a 13% benefit. The above, in the greater, more.
The greater MACE benefit was driven by something else. We think a lot large portion of that could have been the LDL particles.
Understood. That's helpful. Can you remind us of the planned filing timelines and how that relates to when we'll get the PREVAIL data and what might be included in the filing package from PREVAIL?
Yeah.
Great.
I can do that, Aaron.
Okay, go ahead. Go ahead.
The plan's unchanged. We wanna make sure that PREVAIL is in the public domain at the time of launch. This has everything to do with IRA and the world we live in today. We wanna maximize the potential for the drug at the time of launch. With having PREVAIL data in the public domain, we also gain broad payer access. That's the strategy. We obviously will discuss with the FDA the approach we wanna take as it relates to the completion of PREVAIL and when we can file. The goal is to really be able to not only have LDL label claim as soon as possible, but also the CVOT data included in that in that label.
Great. The Menarini EMA approval in the second half.
Yeah.
I guess you don't necessarily need outcomes data in Europe the same way you do in the U.S., but maybe you could talk about the progression of what you expect there, your economics, and could there be any important label differences in Europe versus U.S.?
Yeah. Do you wanna speak to the label differences?
Okay
I can cover the economics and launch?
Well, one thing we do expect in Europe is Lp(a) lowering. They have it for inclisiran, which is Leqvio is in the label, so that's a good one. I mean, FDA, we don't know yet, but, you know, it's hard. The FDA tends to be very conservative on these secondary endpoints. Inclisiran has it. It's one of our, you know, key secondary endpoints in our trial, so we hope it's in the label. That's a key differentiator, and it will be available as the first Lp(a)-lowering therapy in Europe. That's exciting, I think. We'll see how that plays out. Regarding outcomes, by the way, so it comes later in the pricing dossiers.
You can submit your outcome data during the, during the year-long, you know, pricing phase. That's why it'll come out later.
Yeah. In many ways, the agreement with Menarini is ideal from a deal structure standpoint as well as the partner that we have. Just going through the economics with you, the royalties begin at low double digit and go all the way up to mid-20%. Based on the sales thresholds that are embedded in the agreement, we fully expect to be able to get to the highest tier. We're still owed roughly EUR 800 million in milestones. The trigger for those is going to be a combination of regulatory milestones, launch in the EU5 countries, and sales-based milestones in the future.
This is an agreement that where, you know, we expect to recuperate a significant amount of capital, which obviously helps us avoid accessing the public markets. In terms of the partner, Menarini is ranked number one when it comes to primary care cardiology and top three within the endocrinology or the diabetes segment. That's why I said, I mean, we couldn't ask for a better partner in terms of launch capabilities and execution. The dynamics in Europe are different than those that are in the U.S. We are looking at country by securing country by country reimbursement. The initial launch, it will be in Germany, followed by U.K., but the other countries will follow based on securing reimbursement.
The dynamics also are different from a competitive standpoint. In Europe, the use of PCSK9s is relegated to specialists, and that's really limited the rate of adoption and the overall adoption there, versus bempedoic acid, which is more broadly prescribed and has been able to take leading share.
Okay.
That's going to be our goal as well.
That's helpful.
Yeah.
We've got 15 seconds left. RUBENS and REMBRANDT, maybe you could just briefly describe those and the goal of those studies and when we might get that data.
RUBENS is starting enrollment. It's a diabetes trial. We wanna expand our label to not just take ASCVD patients, but extend it to diabetes, which is, you know, 30 million people. It's another big part of the population. Again, this is an ideal population for obicetrapib because it lowers the LDL. They are the ones that have the small particles, by the way. We think it's gonna have good efficacy and an overall great profile for the diabetic patients and expands our label. REMBRANDT is our. The trend in the world is to look at plaque volume now and assess change. It's a great outcome benefit. We're seeing a lot more of these. I'm doing it clinically in a lot of patients.
Showing the patient that your plaque volume is getting better is really a great ocular thing that you can show. Cardiologists love that kind of stuff, where, you know, our oculatory dilatory reflex. You know, we see a lesion, we wanna dilate it. We see a lesion, we wanna see it shrink. That's gonna be our promotional data for the label for showing reduction with our fixed-dose combination.
Great. Thanks for that efficient overview. Before we close out, just, Michael, I noticed, I got one or two inbounds on a stock sale recently, so curious to get your thoughts on that.
Sure. It was my 10b-5, less than 10% of my holdings. My wife made me do it, if you ever have. I didn't wanna do it. I also have 12 grandchildren that I promised to put through college. We also did a grad, which if you know, you know what that means. The grad is set up to, you wanna use a trust to get the upside, and I've done that too with just recently. You can, you can tell my enthusiasm is still there, but, you know, if you're married and you have a wife, you have to also take a little chip off the table for the 12 grandkids, and that's my was my intent.
I get it.
Yes.
I get it. All right, to close out, maybe, you, both Michael, Ian, you could discuss what you believe is the most underappreciated aspect of the NewAmsterdam Pharma story by investors. I think Alzheimer's is a potential obvious one, but curious to hear your thoughts.
I think it's multiple things. One is Alzheimer's. That is a game changer, what I don't think people appreciate is how motivated that population is to be on something that can make a difference, and we think we have that data already in our, in our market research shows that, you know, 30% increase in use just by that data we have already is quite exciting. Also, I think the underappreciation of where the market is going and how big it's gonna be and how important obicetrapib could be as a There'll be other drugs, and they're all growing, they're all gonna do great, but we're the only CETP inhibitor out there that has that differentiated profile.
Yeah. I would definitely emphasize Michael's point on commercial, just the size of the commercial opportunity. I think we all get bogged down with looking at individual product profiles and trying to determine what market share one drug will have versus another or one class will have versus another. The reality is this is a patient population that numbers in tens of millions and could double in size based on updated treatment guidelines, driven in part by the VESALIU.S. data. This is a market that's large enough to support every drug that's in development today and help drugs that are on the market continue to grow as well, and we wanna participate in this in this market.
Wonderful. With that, thanks for the great discussion