Hi, good afternoon. Welcome to the Jefferies London Healthcare Conference. My name is Dennis Ding, biotech analyst here at Jefferies. I have the wonderful pleasure of having NewAmsterdam Pharma here. We have the CSO, John Kastelein, and CFO, Ian Somaiya, here with us. Welcome.
Thank you.
Maybe to kick things off, just talk about obicetrapib as a molecule, what you are trying to achieve with that for those in the audience and those listening who may not be familiar with the story, and what we should be looking forward to in 2026.
Sure, I'm happy to do that. I just celebrated my two-year anniversary at NewAmsterdam. There are these opportunities to reflect on what we have achieved. For a company that's five years plus now in the making, there's quite a lot. As I think about my past two years, during my past two years, we've delivered on three successful phase 3 trials, which gives us confidence that the application that we've put in front of the EMA will ultimately support approval next year and allow our partner, Menarini, to launch shortly thereafter. Beyond the focus on the clinical trials, and obviously there are many that we'll discuss in a few minutes, I'm sure, Dennis, it's the other parts of the organization that I also want to highlight. It's the work that our commercial team has done to establish a global brand for obicetrapib and the fixed-dose combination.
Some of those you've heard from us, some of those we shared during our R&D day back in the summer. Quite simply, as you think about the profile of OB, it does go beyond LDL. This concept of LDL plus is something that is true and is something that we'll continue to speak to when we transition to the commercial setting. It's the expectation that patients should have and caregivers to look beyond LDL because our drug does more than simply reduce LDL. It reduces LDL, it increases HDL, it reduces particles, small particles preferentially. The most recent data we've shared with you is the impact it could have on Alzheimer's.
As I think about the manufacturing organization and the work they've done to not only streamline the process, but also lead to the issuance of a new composition and matter patent last year, which is granted in the U.S., which extends our IP to 2043. Going forward, and more specifically to your question, Dennis, our focus is on continuing to execute, executing on our clinical trials and executing on the global efforts and supporting Menarini in their launch in Europe.
Perfect. One of the biggest catalysts for the company over the next 12, 18 months is obviously the PREVAIL CVOT trial. Talk a little bit about that, your confidence going into that and what underpins that confidence.
Yeah, I think, John, that's a great question for you.
Yeah. First of all, in one of our phase 3 trials, we already saw a 21% reduction of MACE, which gives us, because in that trial, Broadway, we've always designed that trial to be a mini PREVAIL. The trial is four times smaller and it's four times less long. That gives us enormous confidence that the translation of that MACE benefit will actually read through to PREVAIL. Secondly, we have designed PREVAIL with all the mistakes that have been made in the past, like going too short, for example.
In that regard, for us at the American Heart, the Vesalius presentation by Amgen was by far the biggest catalyst for ourselves because it showed that if you lower LDL deep enough and long enough, you'll have an all-cause mortality benefit for the first time for a non-statin drug. That gives great confidence, first of all, is that the market actually is twice as big because you now go into primary prevention, which is good for all companies in this field. Actually, you have to have goal attainment, which is very important for drugs these days. All of that pertains to the read-through to PREVAIL, where we designed the trial to be high risk, we designed it to be long enough, and we use a drug where the LDL lowering is deep enough.
We have been tracking the events, of course, although we have only access to blinded event rates. Until now, everything is tracking perfectly fine. We have to realize that in these outcome trials, in the beginning, the blinded event rates is usually linear. When the drug really starts to kick in, you, at the two-year mark, see kind of a bending of the curve. We will have the two-year mark in April of next year. We have the anniversary of our last patient in two years later. The confidence intervals around the event rates will become very narrow. With much greater precision, we can then say actually when we think that PREVAIL will achieve the number of events.
We should also realize that we've not only said that we want to achieve a certain number of primary endpoints, which is the four-point MACE, exactly the same four-point MACE as Vesalius used. That was also for us kind of certification of what we did. We also want to achieve a certain number of three-point MACE. We've set that bar at a certain number. Of course, for an outcome trial, that can vary by, of course, by a couple of months. We will know that much better basically in the late spring of next year. That will also have the consequence for our regulatory strategy that I hope that Ian wants to express because he's the American. I'm just a simple European.
One other thing before I, and I know Dennis had a question on regulatory timelines. The other thing that gives us confidence is just the quality of the conduct of the study. These are not updates that we can provide to the investment community. As you can imagine, we look at the conduct of our trial and we compare those to other outcome studies that have been completed. At every turn, what we see is a study that's executed to that sort of the highest order. That gives us a lot of confidence in the ultimate outcome of the study being positive. It's the value that we place on every patient, retaining every patient in the trial and motivating patients and providers to really drive compliance in the study.
If we're able to do that successfully, based on the data we've already shared with you, we feel confident that we can deliver on a positive study. Outcome trial.
Yeah. Yeah.
Just taking that last part of the question, the regulatory strategy has really remained unchanged. We're really in an enviable position because of the decisions that John and Michael made very early in the company's founding. Simply put, we started our outcome study at the same time as our LDL studies. The goal is to have outcomes data available at the time of launch, which no other company in the lipid-lowering space has ever been able to do. If we can do that, if we can deliver on that, we believe we'll be able to garner broad access in terms of payers and also drive broad utilization.
From a timing standpoint, once we have the update on PREVAIL, the next big update for us is the first half of next year, we'll engage with the FDA and really ask a question that I think is important to all of us, which is at what point during the regulatory review period, and this is the LDL filing, would they accept the CV outcomes data? That not only speaks to the timing of PREVAIL and the timing of U.S. approval, but our hope that we can get the CV outcomes data in the label shortly after launch or potentially at launch. That is an ambitious goal, but one we think we have an opportunity to meet based on the partnership that we have with the FDA.
If I can ask a little bit about the Broadway, the 21% MACE benefit that you guys saw, I would love to hear your thoughts on how much of that is signal versus noise? Because based off of LDL alone, you guys predicted 9% and there's a 12% delta. That obviously led you guys to be increasingly more bullish about PREVAIL, the CVOT. Also, I'm wondering how much of that is signal versus noise.
That is the third point that Vesalius brought to us. If you go to the New England Journal publication, you can see the Kaplan-Meier curves for both the four-point MACE and the three-point MACE. We have always said that revascularizations are the major part of your MACE benefit in the first year of any trial because that is simply the way we practice medicine. If you have chest pain, you are hurdled into an ambulance, and within an hour, you are at the hospital in the cath lab and you get a stent and the door-to-balloon time average in my country is now two and a half hours. Actually, modern cardiology is preventing first heart attacks by simply rushing patients to the hospital with a revasc. That is something that I said to the investor community at the time of Broadway.
We had no formal proof of that, but now we do have proof because if you look at the Kaplan-Meier curves for Vesalius for four-point MACE, it actually, the Kaplan-Meier curves diverged exactly at six months, which is exactly what happened in Broadway too, while the three-point MACE, which is everything else besides revasc, only separated at one year. In a one-year trial, you cannot show a difference for three-point MACE, but you definitely can show a difference for four-point MACE. The Vesalius curves are kind of, again, a third internal validation of what we've always claimed with Broadway and which gave us this confidence of a read-through to our outcome trial. Now, what you then do, if you look at the Kaplan-Meier curve in Broadway, you can see that nothing happens the first six months, which is exactly what the biology tells you.
It takes time to stabilize plaques. You see the coupler MAIA open up, and it should be more opened at the end than at the beginning. It should not go like this. It should go open and more. That is exactly what happened. What you then can do is you put these events into a mediation analysis, and you question the database and you say, what does explain the benefit in the treatment arm versus placebo? You can do lowest regression curves. What came out is that there were three things responsible for the majority of that benefit: LDL, of course, intuitive for 9%, and then the rest for a majority was both Lp(a), lipoprotein(a), and the small particles. Now, I have to explain a little bit about small particles.
Your LDL cholesterol is carried by particles, and part of those particles are large and part of them are small. In people like us, we hardly have any small particles. The moment you're getting insulin resistant or diabetic or prediabetic, or you take high-intensity statin therapy that removes preferentially the larger particles, you're stuck with the smaller ones. The smaller ones are easily oxidizable. They can more easily penetrate the arterial wall. In general, they are the lousy particles that you want to get rid of. What we saw is that part of that 21% could be explained by lipoprotein(a) and our quite excessive small particle reduction. A CETP inhibitor removes more small particles than large particles. The opposite is actually true for statins.
That's why I think, and I think more with me, is that obicetrapib is such an ideal companion to statins because statins increase Lp(a) a little bit. They increase type 2 diabetes risk by 36% if you're on 80 mg of atorvastatin, and they preferentially remove large particles and leave behind the smaller ones. We think that that 21% is explained by that metabolic profile. Now, there are confidence intervals around those numbers, of course. I mean, I give you a point estimate, but there are always confidence intervals around it. There was a little bit of room left for something else. That something else could be partly due to some other effect.
What is so intriguing about CETP inhibition is that after we did that mediation analysis for what explains the MACE benefit, we then started to analyze the Alzheimer's disease biomarkers and we found a positive effect there as well. CETP inhibition, because it so fundamentally changes lipid and lipoprotein metabolism, has a much wider array of effects than simply a statin, for example, or a PCSK9 that have a mechanism that just lowers LDL cholesterol and nothing else, which is great, but that is, it is more simple to explain than a CETP inhibitor.
Okay. In terms of the small versus large LDL particles, how well accepted is that concept or hypothesis by the scientific community? Maybe remind us about the Framingham Offspring Study. What gives you the comments that would drive an outsized benefit in PREVAIL?
The Framingham Offspring Study was an observational study in a small town in Massachusetts, which I do not think is very representative of current-day cardiology. I think the U.K. Biobank is much better. It is 550,000 individuals followed up for 17 years with 60,000 events. It is huge. What you can see, LDL basically is representative of particles. It is not the cholesterol that matters. It is the particles that matter. There is ample data, I mean, a lot of biology and a lot of epidemiology and also Mendelian randomization studies that show that the smaller the particle, the more easily it is oxidized. It can penetrate the arterial wall. It sticks to proteoglycans. It starts the plaque. There is more than enough biology and also epidemiology, especially very recent epidemiology, that actually tells you that small particles are worse than large particles.
Now, of course, if you have a huge amount, like genetic high cholesterol, if you have a huge amount of cholesterol, then you have both particles. It is especially true for people that have relatively normal LDLs, but they are insulin resistant or diabetic, that that cholesterol, what you measure, is mainly carried by small particles. We all know that the diabetics are the ones that suffer most from particles, from LDL cholesterol.
Got it. In terms of PREVAIL, and that data is potentially late 2026, maybe early 2027, what do you think is a clinically meaningful benefit? What do you expect the data to look like? I guess commercially, does it even matter if it is 15%, 18%, 20%, or do doctors just focus more on LDL or safety or some other parameter?
There are two sides to that answer. I think first of all, the main thing is that we need a successful PREVAIL study, meaning a reduction that has a statistically significant p-value attached to it. I think that we can, with really considerable certainty, say that after Vesalius and after our Broadway data, that we are pretty sure that we're going to have a positive outcome trial on our hand. Interestingly, when you're now, and now I'm a doctor, I was heading the largest prevention clinic in Europe for a very long time, thousands of new patients per year. When you have a patient in front of you, what you get as a doctor is a lipid profile. I mean, you all know that. I mean, you get a number for LDL cholesterol, for HDL, for triglycerides, for lipoprotein(a), and for CRP perhaps.
What you treat is to goal. You look at the guidelines. Many doctors have the guidelines attached to the wall. Okay, this patient has moderate risk, so less than 70. This patient's very high risk, less than 55 mg per deciliter. What you do in practice is you treat to goal. In order to understand which drug gets your patients to goal, you look at the New England Journal and the JAMA publications, and you look at the bars and see what percentage are brought to goal. For that principle, it is less important if it's 18%, 19%, 20%, 21%, or 22%. In fact, that doesn't matter anymore. Of course, it shouldn't be 11%. If it's 35%, it's fantastic. There are ends to that debate. That hovering around the 20% is a strange debate because that won't matter anymore.
I mean, look at the PCSK9 inhibitors. They had for a decade, they had a 15% benefit, and it's a $5 billion class of drugs right now. People, if you ask a doctor, what is the MACE benefit of a PCSK9, everybody will say, well, somewhere in the 20s. People also, I mean, that is not a number. That is actually something that you reminisce about. It is the goal attainment that actually is the practical translation of what your drug does. Our goal attainment in the TANDEM trial, which was published in Lancet, our phase three trial of our fixed-dose combination, was like 70% for less than 55 and 80% for less than 70. Those are then the numbers that become important for patients.
Probably the one thing I would add is, and John, obviously, you're speaking to this as a cardiologist with quite a bit of experience dealing with this patient population. The other segment of our target audience from clinicians is primary care. I think we all have experience with our own primary care physicians and the minutes that we all get to spend time with them and address many of the things that we need to. The simplicity of the product and the product profile, once a day, low dose pill, well tolerated. I would add to that the consistency of the benefit across patient populations. Whether you are a patient who has diabetes or some other comorbidity, whether you are on a statin or a statin or ezetimibe, there's a predictability to the benefit the drug provides.
That reduces the amount of time a clinician would need to spend with their patient. I think that is the other aspect of the drug that will resonate with clinicians on top of the characteristics of the drug that go well beyond LDL reduction.
Got it. AHA was just last weekend.
Yep.
It was great seeing you guys there. I would love your perspective on the Merck's oral PCSK9 data. Did it come in line with your expectations, within your expectations? How do you think about the eventual commercial positioning of obicetrapib relative to the oral PCSK9s?
I'll leave the commercial positioning to him. PCSK9 is a trusted, old, reliable mechanism of lowering LDL cholesterol. I have to take my hat off for Merck for executing so incredibly well with a novel way of administering a PCSK9. That is not that simple. You have to fast for eight hours, sit at the breakfast table, and then 30 minutes later, take the drug, and you can't even have a coffee. It is really, and they had really good adherence in those trials. They have to be really applauded for that.
The expectations were met completely because basically they did exactly the same as in the phase two, which was robust LDL lowering, side effect profile, uneventful, except for the gastrointestinal events, which are intuitive because sodium caprate is known to irritate your small intestine. You will have some diarrhea and some gastrointestinal complaints. For the rest, PCSK9, we know that we can do without PCSK9 because there are companies who are gene editing it. I mean, lowering PCSK9 does not lead in humans to any specific problems. If you inject it with a needle, it is the needle that gives you the side effects. If you are taking it with sodium caprate, it is the sodium caprate that gives you the side effects. In that sense, I think those were two very good trials.
I think what you do see, which you did not see with the monoclonal antibodies, if you look at the ASCVD trial, is that the initial efficacy was 55% and the end of the trial was 47 point something. That has nothing to do with PCSK9 getting less efficacious. I think that has everything to do with adherence. People find it quite difficult to adhere, I think, completely to this regimen over time. I think what we also need to do is to wait for real-world trials. As we have seen with Inclisiran, for example, I ran the entire Inclisiran phase three program, 52% LDL lowering. In the moment the Germans do some real-world trials, it was much less than 52%. Real-world trials give a better indication of how well patients adhere to the drug. What I also kind of miss is the MACE data.
What I would have loved to see in the ASCVD trial was because Merck should have had, or the trial list should have had basically the same number of events as we did in Broadway, the risk of the populations did not differ much. I would have expected them to present the MACE data because the MACE is seen by the regulators as safety. It is not an efficacy outcome. It is a safety outcome. You want to be complete in the reporting of your safety outcome. That is still something I cannot assess because the data was not presented and the New England Journal is not there yet. That I cannot say. In terms of the positioning, I will gladly give the word to my friend Ian.
All right. I am happy to speak to that point. Let's speak to similarities first. Merck's going to launch and their product point of differentiation compared to the PCSK9 drugs that are in the market today is route of administration. I think we all generally believe that pills are preferred over injections. There is a reason why, despite the dramatic efficacy of the PCSK9 class, the usage is limited to roughly 1 million patients. I think Merck will solve for that with the delivery of oral. The other is the point that John, you made earlier, which is getting patients to goal. They reported an ability to get roughly 70% or 80% of patients to goal depending on the threshold we are looking at. That is exactly what we have reported in our TANDEM study. Actually, our numbers were slightly higher than what Merck reported.
Let's walk through the differences now. There are many. When you look at the patients with hypercholesterolemia, the vast majority of them also have diabetes or prediabetes. Those numbers are 30 million patients each. There, we've seen in our study, in the Broadway study, which is just a one-year study, a decrease in the rate of new-onset diabetes. That's something that we've seen consistently with the CETP class, which we have not seen with others. We've also shown a 45-50% reduction in Lp(a). Again, roughly twice as much as the PCSK9 class. We've also seen a benefit in terms of kidney function in our phase three studies. The other benefit that I think we should spend time on is on the Alzheimer's. There are many reasons for a physician to prefer obicetrapib.
Those are going to be the positioning of the drug that I think will ultimately resonate and will serve as points of differentiation versus what's available to patients today.
I also think is that there are 30 million Americans who are not at goal today. Vesalius made that 60 million. Vesalius basically, by putting the bar really for everyone at 55 and actually putting it before a heart attack, kind of doubled the target population. That population is so immensely large that you could also think, why do we speak about competition? I mean, there are so many patients. If your drug is very well differentiated on a number of points, Merck undoubtedly will be very successful in this area. I think there's just as much evidence that we will be very successful too. I don't like to think about it as competition. Merck will open up the market more and will be basically also saying that orals are a good thing, which is, of course, what we have been saying too.
Yeah. Yeah. Makes total sense. I'm afraid we are out of time. I wish we had full 60 minutes. I feel like we can talk forever. Thank you so much, John, Ian, for joining us.
Thank you.