Is it right next to you?
Yeah.
Well, good morning, and thank you for joining Guggenheim's 2025 Healthcare Innovations Conference. I am Debcet, and my privilege to welcome our next presenting company, NewAmsterdam Pharma. And joining from NewAmsterdam Pharma is CEO Dr. Michael Davidson. Thank you so much for making time for us.
Thanks, Debcet.
I know you're coming out of a very interesting AHA. Before we get to the core of the NAM story, maybe your quick takes from the AHA and how that sort of helps out the NAM story.
All right. So for me, it was a very exciting meeting. I'm a lipidologist, cardiologist. And so what has been kind of holding the field back has been this lack of evidence on mortality of adding to statins. We had statins, the 4S trial back in the '90s showed that simvastatin reduced mortality in a very high LDL population. And that took the statins then took off after that and became the major drug to reduce LDL. And then over the last several years, there's been this concern that once you add to a statin, you really, in fact, get a mortality benefit. And then Fourier came out. And in hindsight, as you may recall, Amgen wasn't even sure whether the drug would be approved or path would be approved prior to outcome studies.
So they decided to basically load it up with almost 30,000 patients and get the answer as quickly as possible. And they got a positive benefit, but it was modest, 15%, and no mortality benefit. And so there's been the critics have always said, what do you really accomplish with LDL lowering on top of statins? You don't prevent mortality. So VESALIUS showed a mortality benefit in a lower risk population. So that took the monkey off our back regarding, let's get LDL lowering more effective in practice. Now we have not just the post-MI, post-stroke population having a benefit. This study was a broader population. They could not have had a stroke or heart attack, but they had to have evidence of either plaque, like a stent, or high-risk diabetes, over 10 years of diabetes. So really, the major take-home arguments is now we have a mortality benefit.
There's no reason not to treat aggressively. And now we also have evidence that getting below 55, even below 40, makes a difference. So for me, what this means is that we're now going to see guidelines shift to get even more patients to be treated aggressively. And we have greater confidence in the evidence of benefit on mortality. So it's going to really open up the whole lipid market. Guidelines are going to be revised. And so we're going to start seeing a real new push to get LDLs below 55 for all high-risk patients. And that high-risk patient definition has now been markedly broadened. And so that for us in New Amsterdam opens up another very large market segment that we can use, hopefully, when we launch our drug in the not-too-distant future.
And the other thing that I found striking from the Repatha data when I look at the MACE-3 versus the MACE-4, the early separation in MACE-4.
Yes.
That was something that you guys noticed with the BROADWAY study. And I don't think critics bought into it. But now with the Amgen data, does that change mindsets?
I think, again, it's all about understanding the cardiovascular event world. I mean, today, when you have an event, it's most commonly a revascular event. And if you get to the hospital soon enough, that chest pain goes from an MI to a revascular. And so then you stop the heart attack. You stop with the revascular. So the revascular becomes the first event that you see in a patient population. So stopping revascular or reducing revascular, like we did by over 30% in BROADWAY, is what you expect to see in the shorter term of the study. As you go longer, you start seeing the heart attack reductions go down and stroke and all the other things happen later. So that's exactly what they saw in VESALIUS. The first year, separation was driven by revascular, like BROADWAY.
Over time, you saw the other events start to, by the way, I don't know if you know how this works, but if you had a revascularization and then you had a heart attack like a year later, the four-point MACE counts as revascularization. But the three-point MACE, then you don't have the revascularization in your three-point. Then it becomes an MI event. In other words, whatever we take first to event, you take out revascularization then. The events happen, as you can see later, with the three-point MACE. That was also 25% benefit in VESALIUS. It went longer. The learning for us is we really feel good about our PREVAIL design. We maximized the LDL levels at baseline, similar to what VESALIUS did. They went 4.6 years. I talked to the investigators afterwards.
They think that four years versus 4.6 years, four years didn't seem to be they got the greatest benefit really about four years. And so we think that that's about what we expect our median follow-up is going to be as well with PREVAIL. So it really gives us a lot of confidence that PREVAIL is going to be, as we had hoped for when we designed it. VESALIUS gives a lot of, again, even more and more evidence we designed the right trial for the drug.
Appreciate that. And then quickly on the Merck oral episioskinine data, does that change your thought process at all from where the competitive threats could be for obicetrapib post-PREVAIL?
Sure. Yeah. So the Merck data was good. It was exactly in line with expectations. They saw LDL lowering of like 56% at the primary endpoint and then 47 at day 365. So right in line with expectations. It was very, they made the point that 97% were adhering to the regimen, the fasting for eight hours and nothing within 30 minutes. And I think that's what you can do in a clinical trial. But the best example is RYBELSUS. RYBELSUS is the oral GLP-1 by Novo Nordisk. They had 90% kind of compliance in the studies. But when they went to the real world, it's more like 40%. Only 40% comply with the dosing regimen or long-term utilization. So I think the real-world data will probably slip a bit when they get out in the real world.
More importantly, I think it really emphasizes why we're moving to orals and why orals are important. Merck being in the market to us is a great, it's great to have them in the market with us to highlight the benefits of LDL lowering and getting more people to goal. However, when you put our drug side by side to an oral PCSK9 of that formulation, we have to take after eight hours of fasting and not within 30 minutes. If you have a lot of other drugs, doctors much prefer ease of use, just give our drug no matter what, any time of the day. Our 50% lowering with our fixed dose combination is very close to their efficacy. So we don't see that being a major differentiator on their side.
For our side, we have the Lp(a) lowering and the diabetes benefit and the small particle reduction of 90%. What we've heard very loud and clear from the KOLs is they really, really appreciate the Alzheimer's benefit. That is one of the more kind of innovative values that obicetrapib brings that they don't see in any other therapy. So we think that's going to also drive a tremendous amount of uptake. And so at the end of the day, it's the LDL plus benefits with obicetrapib that's going to make the difference in the marketplace. We're all going to do well. The market's growing. It's getting bigger. And as you know, the analysts are predicting $4 billion-$5 billion for both Merck and AstraZeneca.
And we feel, based on our data, we're at least in line with that type of uptake based on all the new things that are happening in the lipid world.
And where does the fixed dose combo of OB and ezetimibe fit in versus the Merck data?
So it's very similar on LDL. So we're at 50%. They're at 56. So it's roughly the same. Again, a lot more ease of use with the fixed dose combination. And so again, we have LPLA lowering. It's going to be greater. No food effect. So I do think the FDC will be a real go-to. Also, keep in mind about 25% of patients that need more LDL lowering are already on ezetimibe. And so it's another easy to switch them from ezetimibe to the fixed dose combination also.
Got it. So let's talk about PREVAIL. The events are tracking just as you guys planned it. Data end of next year, give or take a month or so.
Yeah.
What do you need to demonstrate from the PREVAIL study for OB to become our prescribed ahead of the non-statin?
Right. So I think, first of all, I just want to clarify one point. So we have a two-and-a-half-year minimum follow-up, which ends October of next year. But it is event-driven. So we have to get the predetermined events. We haven't announced exactly what the event rates are. We're getting final feedback from the FDA. But there is a good chance it'll go later because the two-and-a-half years will not be the gating. It'll be the event rates that we have to achieve. So it could go a little bit longer into 2027 for the study completing. And we want to give it time. That's the thing. We don't want to rush the study. That's our prime value creator for the company. And I think people have made mistakes by trying to rush these studies too quickly.
So with the event rates tracking, we tracked because it's very much like the Fourier population was designed with that population in mind. So we know pretty well what the placebo event rate should be. And so we're tracking that. And we're seeing how it plays out. And so we'll know we want to update the investor community around April, May, maybe June of next year, exactly more on the timing of when PREVAIL is going to complete based on what our event rates are showing.
Got it. And the placebo event rates are tracking like you thought?
Well, we don't know the blended event rate.
Okay.
We don't know the, obviously, we don't know the placebo event rate per se. But we know the blended event rate. Yeah. So with that in mind, we feel really good about the BROADWAY 21%. We feel really good. That's what PREVAIL's translating to as we track events.
Got it. But the study was originally powered at, if I'm not mistaken, 17%?
Yeah. We actually go down as low as 15%. So as a.
But you guys feel confident you could see a 20%+ benefit given?
That's based on what BROADWAY showed already. And it all comes down to what the plus benefits contribute to the outcome benefit beyond the LDLC lowering.
So let's talk about the plus benefits, right? You had your classic LDLC on the regression line.
Right, right, right.
But then you had another pretty significant additive benefit from elimination of the small particles, LPLA. So have your thoughts sort of refined on the small particles?
Well, it's really hard to separate the two things out, the small particles and the LPLA. And it both happens in a very robust fashion. But the LPLA benefit is obviously in the patients that have high LPLA. And that's the subset that have between 50 and 150. So that's a subset of the overall population. And the small particles, though, apply to everybody in the study. Everybody has this very 90%+ small particle reduction. So I know we have this debate, is it small particles, is it LPLA? But I think at the end of the day, they both are going to be important contributors to the LDL plus benefit. And so we'll know more when the study completes. And we can start looking at, we already have pre-specified certain subgroups to see the best benefit.
What we do know in all the other CETP inhibitor trials, the diabetic patient population do have a relative risk reduction that's greater than expected. And they're the ones that have the most small particles. So that's a clear benefit. Even for all the CETP inhibitors that have been studied to completion, we see that benefit.
Got it. And do you have a sense of what percentage of patients have Lp(a) between 50 and 150 in the study? So that's where you had the max benefit.
Yeah. It's about, so the median Lp(a) in the trial is around 40. So 50-150 is probably about a third of the patients. That makes sense.
Got it.
Okay.
You talked about the risk reduction in type 2 diabetes. How important is that for the overall profile of the drug?
I think it's really important. I mean, we have a very high % of diabetic patients in PREVAIL, even more so than BROADWAY. So that gives us more optimism, again, about the drug working. So we are doing another study called RUBENS because the drug does work better in patients that have more small particles. It kind of makes sense. More small particles means more CETP activity or vice versa. More CETP activity means a lot more small particles. Those are the diabetic patients. And so we have a drug that has this great benefit on reducing the cardiometabolic profile of those patients, less small particles, less progression of diabetes, less renal disease, all that was shown in BROADWAY. And so we feel that that becomes a really important kind of, again, a plus benefit for all the diabetic, the cardiometabolic patient.
We think obicetrapib is well suited to address all those comorbidities that lead to increased CV and total mortality.
And if the event actually was a little bit slower at the back end of it, what happens to the timing of your NDA submission in the U.S.? Because wouldn't you want the PREVAIL data available at the time of?
Launch, yeah.
Yeah.
So yeah, we're going to go meet with the FDA sometime next year for our pre-NDA meeting. And we want to try to, we're not rushing to do that either because we want to get a better understanding when PREVAIL is going to complete. But our plan has always been to file knowing that during the FIDUFA period, PREVAIL will complete. And that's how we want to time the filing.
Got it. So second quarter filing next year might make sense because you still will be in that PREVAIL should read out.
Yeah. We're going to give more guidance to that sometime next year. I think we want to get even more and more clarity on the events where they're tracking. We'll be able to get back to the investor community and give us a sense of when we will file. We also need to get from the FDA their view on when we can file the outcome study during the FIDUFA period and what that may trigger regarding a major amendment or things like that because we ultimately want to have the outcome study published in the public domain or in the label when we launch. And so we want to try to understand what that means from a commercial perspective.
Got it. And the VINCENT, RUBENS, and REMBRANDT, any thoughts on timing on those?
Yes. So VINCENT will be next year. RUBENS will be, we're pushing for the very end of next year for RUBENS. And then we do have REMBRANDT, which is an imaging study. It's going very well. Enrollment's going very well. So it's an 18-month trial. So that's tracking to complete right around the same time as PREVAIL. And we'll get back to the medical community later next year, early next year. But we are considering another Alzheimer's trial, a true prospective Alzheimer's trial that looks at the subgroup within BROADWAY, which had the greatest benefit, which we're very excited about because it's the high-risk group, those that have E4 genotype and elevated PTAL baseline. They have tremendous benefit in our BROADWAY data. We now want to show a prospective trial that also will read out around when PREVAIL reads out.
So everything is at the end of the; we're talking about when PREVAIL finishes. We have hopefully a positive outcome study. REMBRANDT finished. RUBENS finished, all going into our label. We'll have a very prospective trial with showing p-tau, a very good biomarker for amyloid in the brain, showing a benefit there, and there's also the PREVAIL biomarker data on Alzheimer's that we can release, so we're going to have, I think, a very, very, very strong case for why obicetrapib should be the go-to drug for anybody that has high risk for either heart disease or Alzheimer's disease.
The other prevailing question out here, obviously, is can NewAmsterdam launch this drug or launch obicetrapib themselves given you're going up against Big Pharma? So thoughts on how you're prepping for the launch?
We have a great team, BJ Jones, who launched Nurtec for Biohaven as a small company, beat AbbVie with, I think, and he feels very strongly that our differentiation of OB versus what we're competing against is even greater than what he had with Biohaven. He has got a more differentiated drug. We are looking at all kinds of different ways to think about the launching of the drug. We are all about creating value with the drug itself. Our next execution is really enhancing the whole profile of obicetrapib, which will either help us launch successfully or if we have a partner, they'll also be more excited to launch a drug and give us greater value as well.
And Menarini has already filed in Europe.
Right, right, yes.
Do you think PREVAIL would be a holdup there for utilization?
They're not waiting for PREVAIL to launch, yeah. So they're going to launch before PREVAIL.
And from a payer restrictions perspective in the United States, given all the new agents which will be launching, let's say, in the next three to four years, how do you see all this play out, especially if you're right that the whole thing moves frontline, more aggressive LDLC lowering?
Right. All the different drugs out there?
Yeah.
I really think we're going to be in a new golden age of lipid. That was one of the themes of the American Heart, actually. People got up. We're entering another golden age of lipid cardiovascular risk reduction. And the tools that we're going to have anywhere from much better lipid management for LDL, LPLA, triglycerides with all the other agents that are coming, the GLP-1s, all the different ways of delivering GLP-1, especially the oral therapies. We really feel that we can transform the field. Leading cause of death is still cardiovascular disease. But I do feel that we can make a big difference with what's coming down the pipe. And like I said, lipidology, I still see patients four days a month at the University of Chicago. I have a waiting list of a year now to get somebody to see me.
So it's becoming very, very, with all the different therapies, you would think it would, but we're seeing that we're now much more excited about what to do on prevention. And so now better imaging, we're seeing a lot of technologies trying to look at plaque and plaque characteristics. So I'm really, really excited about where the field is going. And I think we can make a huge impact on heart disease in the next 20 years with what we have becoming available to us. And of course, not even thinking about the gene editing approaches, which I think will take time to really get commercialized for sure. I think a lot more safety, we have to get a lot more safety data there. But I do see a very bright future ahead for where we're going in the field.
Well, awesome. Thank you so much, Michael. I'm looking forward to a really interesting 2026.
Yes. Thank you .
The data has sort of evolved really well for you guys.
Yeah, perfect. Thank you.
Thank you so much, Michael.
Bye now. Thank you.