NewAmsterdam Pharma Company N.V. ($NAMS)

Michael, welcome. Notes -- can I give you the opportunity to maybe just level set us and make some opening framing remarks on the company.

Sure. Thanks. Thanks, everyone, for being here. We've had a really productive year firing on all cylinders. I mean our -- all our trials are rolling along on schedule or ahead of schedule. Of course, the most important being PREVAIL, which is our 9,500 patient outcome study and I think we announced just a few months ago that we're going to do an interim analysis based on a number of factors, we can go into more detail, but that inter-analysis we'll start the actual point at the end of this year, the readout will be in the first quarter of next year.

Well, that's, I guess, one of the most -- that's a great segue into what I think is probably going to take a lot of the discussion, the PREVAIL trial, given how important it is. I want to just maybe double tick a little bit more on the interim analysis. I think just first is on timing. You said it's going to be done by the end of the year with the results in the first quarter.

Well, you said event rate time point, which is going to be the end of this year approximately. And then it takes time to adjudicate all those events and go to growth before the DSMB, and then they have a charter, which they -- guides them on whether we hit the criteria for stopping the trial at that point?

So walk us through, Michael, the decision to introduce this interim right now? And I know you guys have talked quite a bit about it, but I just would love to just hear the framing again, how did you weigh getting to market potentially a year earlier versus the risk of potentially also jeopardizing the trial?

Right, right. We're not jeopardizing the trial in any way. In fact, just to go back to the -- it's really important to go through the history of PREVAIL. When we started the trial, we also started our 3 LDL trials at the same time. So Brooklyn, BROADWAY, TANDEM and PREVAIL all start at the same time. So -- and basically, we didn't have the funding to finish them all, especially PREVAIL. So we were a private company. And our plan was to get our Phase III readouts and then raise more money to finish the trials accordingly. So we went public, we raised the money. BROADWAY worked out well, but we purposely designed broad way to be a mini prevail. And in fact, for the first time, and a lot of companies have a copy of this sense is that we made the Phase III trials very heavily weighted to BROADWAY on numbers. So 2,500 patients in a single trial, all at high risk to give us a large number of events in a single trial in Phase III LDL that we were hoping would provide a lot of support for prevail working. It was designed as a mini prevail. And so it all worked out very well in that regard. We had 2,500 patients. We had a large number of events, again, larger than any other Phase III lipid trial done to date over -- well over 100 events at 1 year. And we solved this 21% relative risk reduction of our new 4-point MACE. We've also had decided that BROADWAY byway would be informative on the final design of PREVAIL because we had initial 4-point MACE that a lot of companies had used, which was urgent revasc cardiovascular death, nonfatal MI and total stroke and that's used. In fact, Horizon is using, I think, the similar. We powered it for 20% relative risk reduction. So roughly 1,000 events, 1,000 events, 20% relative risk reduction. Once we had BROADWAY, and we looked at the event rates and we saw that the 4-point MACE that was now being used more in more recent trials, like clear outcomes, FOURIER and so forth. It's also the CTTC definition of 4-point MACE that's being used for all the analysis of all the LDL trials. We came to -- that was also where the 0.79 hazard ratio was present. So we made the decision, we announced that a year ago that we're going change our 4-point MACE to that 4. So that is -- BROADWAY is very informative on letting us know that, that was the 4-point MACE that was recognized as now the new appropriate 4-point MACE for the recent trials, and it was also our best hazard ratio in the BROADWAY data. Again, all the events were in the right direction except for stroke. But so that provided the best benefit for us in the BROADWAY trial. So with the very large number of events and the 4-point MACE rate, we decided -- we raised a lot of money. And now we had enough money to go longer to make sure that we powered the study not for 20% relative risk production, but now 15% relative risk reduction. So with that in mind that we would now want to go to 15% relative risk reduction power because keep in mind that all the recent LDL trials range from 9% to 15% on their primary endpoint, 4-point MACE. Ezetimibe being 9% and Repatha and alurocumab and evolocumab, Repatha and PAION at 15%. So we felt that 15% be powered with strength of the trial significantly. But with that requirement to go to 15% power, we knew because we were limited by patient numbers were already fully enrolled. We have to go longer. So we're going to go longer. We also have more events now because the 4-point MACE that included total also gave us about 20% more events. So we put in the new event rates, the new 4-point MACE, that gave us more events. But now we decided to go longer to power the study to 15% relative risk reduction. In the meantime, we're tracking our blended event rates, and we're seeing that the blended event rates are much lower than expected using, again, BROADWAY as our benchmark of what the event rate should be, because again, BROADWAY and PREVAIL have the same patient population, the same DSMB, the same adjudication committee, many of the same sites. So if any study could tell you what your placebo rate would be and your outgoing outcome study would be BROADWAY. So BROADWAY should be a really good, strong predictor of what would happen in PREVAIL. So knowing the event rates in Broadway and knowing they have very similar trials. We can make predictions about what the event rate should be in PREVAIL. And we're seeing lower-than-expected event rates, which is consistent with that 21% relative risk reduction. So if that's the case, then an interim analysis at that point that we designated would give us enough power to stop the trial with our -- with the P values that we selected, which are which are important for regulatory approval for both 3-point and 4-point MACE, and that would get us back on track for that timing of approved -- finishing the trial in the first quarter of '27. That's a long answer to your question.

No, it's actually a great answer because I want to stay with Event fed, believe it or not for a second because you've stated that the blinded event rates are dropping in and even more than the expected placebo decay. So I guess what gives you confidence that this is being driven by obicetrupib's benefit rather than the placebo outperformance -- or changes in the standard of care. So -- and maybe also just while we're on that thread, talk about some of the analytics you did with other studies that helped lead to that decision. You touched on this a bit, but let's keep going.

Yes. So like I said, we looked at the first year event rates with PREVAIL and they matched almost exactly the BROADWAY 1-year event rates across the board, 3-point MACE, 4-point MACE, death, nonfatal MI, all the events, all the composite events match very closely to prevail. So we felt that, again, the way it was an excellent kind of guide to what would happen. Now historically, what happens with placebo event rates across 14 different trials. We know there is a decay, but this was greater than expected decline in event rates more than expect from a decay over these multiple trials. And again, 14 trials, we can measure to predicted decay. And like the famous line for us at least, is a good way to lower your risk of heart disease to be a placebo in a cardiovascular outcome trial. I mean, so that's the -- obviously, that's an issue that we were we know about and we're aware of. But even with that in mind, we're seeing this decline in event rates going forward that would be more than expected and consistent with that, what we saw in the BROADWAY relative hazard ratio benefit. And so that gives us, again, confidence on that BROADWAY does accurately predict PREVAIL and that this decay that we're seeing is more than expected from all the other trials that have been out there. We're not seeing -- we've been very carefully monitoring drop-in, dropouts add on GLP-1s or SGLT2s or PCSK9s, and we're seeing very low single-digit drop-ins to any of these that would affect the event rates. And so in that sense, again, we feel the most likely explanation is that obacetripub is validating the 21% relative risk reduction we saw in the Broadway study itself. We also looked at 14 different trials for all CVOTs of recent vintage. And again, we know the decay rates, we also know that our event rates even when you -- especially when you adjust for our risk because we designed PREVAIL to be a high-risk population, high LDLs over 100. All patients have ASCVD, 50% have diabetes. So you look at select, for example, LDL was 80s and the event rates, and we know were lower than you look at other trials that are done in a contemporary time that's relatively recent. We're seeing event rates that are lower than those annualized event rates in PREVAIL. So again, we feel that this interim analysis gave us a 2 shots on goal approach that we -- at the end of the day, we made the study a lot more highly powered for 15%. That's our primary objective. We don't want the study to fail the drug. So a day -- so we knew that would take an extra year, even though we modified the 4-point MACE because the rates are slowing down. But this lower event rate is giving us, again, encouragement that the interim could stop early the trial and give us a chance to be on the market on you're ahead of schedule.

And then maybe on the MACE endpoint change, the 4-point MACE, you changed the point MACE definition from urgent revascularization to total revascularization or CTTC definition, which adds roughly 20% to 24% more events I guess why was that change made? Talk a little bit about that? And how does requiring MACE 3 as well as MACE4, at the interim effect the likelihood of an early stop.

Right, right. Well, so again, the 4-point MACE was driven by 2 reasons. One is BROADWAY, it was as good as urgent and elective for the same hazard ratio. Again, clear outcomes and facilities are all both using total rebase. They saw no difference in urgent versus total. And so that to us is kind of a simple reason to go with the total revas as opposed to urgent. So that made a lot of sense. And so -- and then again, the CTTC definition also using also revasc, which is the net trial use total revasc. So that gave us again a guidance there on that. That test was a pretty easy decision. And also just keep in mind that the big studies recently done, both one's called Courage, one's called ischemia cardiologist, they both showed that using medical management versus a stent, there was no outcome benefit. So the care has changed in the last several years where revasc is becoming much more evidence-based decisions like instead of seeing a lesion and dilating it. There's -- you got to have symptoms, you have to have new onset of symptoms or symptoms that are getting more severe before you get a stent foot in, even payers are demanding more validation of medical necessity. So the blurring between elective and urine is much less than it used to be 10 years ago.

And then I guess on the MACE 3 requirement, why is hitting MACE-3 a requirement to stop at the interim but not strictly for the final analysis? And how much of a second year event decline is coming from the 3-point components, which is nonfatal MI stroke depth.

So it's actually really good. That is our own again, our own conservative thinking on the 3-point has to hit also because even though the primary endpoint is 4-point MACE, in Europe, in particular, regulators like to see 3-point MACE positive. So we would hate to have a situation where the -- the 4-point hit and the 3-point did not and that would -- and so we don't want -- that's our secondary endpoint. And there are a lot of academic schools of thought, even the FDA itself, they've never been an example where this has happened, but if you hit on 4-point, but did not hit on 3-points, then your the regulatory certainty is in question. So you want to hit on both. And so we felt that if we're not going to -- if we're going do an interim analysis, it would be easier not to have 3-point in there to stop the trial. But for us, that would be an unfortunate situation, if 4-point hit and 3-point did not. So we want to make sure 3-point hits as well. Now the threshold for 3-point hitting is not as much as the 4-point because it is the secondary endpoint, but it's still a very significant p-value to get to stop the trial. So that part is -- it's more of a we don't want the study to fail the trial. So if we could have gone a year longer and hit the 3-point and we stopped for that reason, we would have regretted that decision. So we want to make sure that both 4-point and 3-point hit at interim to stop the trial.

Very clear. Let's maybe start bridging into the commercial opportunity. We've spent a lot of time on the trial. But I guess regarding the ultimate MACE level benefit achieved, you've stated that it doesn't really matter what the ultimate benefit is, whether it's 10%, 15%, 20%, why would you believe that to be true from a commercial perspective.

Well, that's just what the -- all the data tells us -- 1 thing I want to make also a point I forgot to you asked about it was the 3-point MACE reduction that we're seeing in we're seeing all events going down, but in particular, the 3-point MACE. And then that's giving, again, encouragement on the whole thing. Now regarding the commercial benefit of 20% versus 15%. We really don't see that driving uptake that much. I mean, it has some impact. But most clinicians, there is -- and based on our surveys, there's 10% of physicians who care about what the percent MACE benefit is. But yet, most doctors, all they want to know is the study is positive or not. All guidelines want to know as the study is positive or not. Like for example, the new guideline just came out, they rank Repatha, Praluent and bempedoic acid, Nexletol as the drugs that go to because they have outcome benefits. They don't talk about the relative risk reduction of those drugs. So this have evidence base of benefit. So for most doctors, they don't even know. In fact.

Also you're saying this could just -- even if there is something that emerges out of that, this is something that could eventually expire in 3 years -- or just we feel that.

We have a lot of good arguments. It's not our -- we have no control over pricing in Europe. We have arguments that we can make about why that wouldn't affect us. But nevertheless, we are working closely with Menarini on how best to approach the the pricing in Europe. .

Okay. And then maybe on the U.S. side, Michael, can you file the U.S. application ahead of the interim readout? Is that -- I think that's the strategy.

We potentially, we're talking with the FDA and we're actually -- we're blessed at the FDA with the same team we've had for 5 years.

And how are those discussions going?

Going well. I mean so we both have the same objective, which is that we want to see the drug on the market with outcome data already in hand. And so they -- we both have the same objective that we want that. They want that. So we're working together on how best and how to time that effectively.

Okay. Let's talk a little bit about Lp(a) and Horizon. You touched on this briefly aloha had some conversations about this in the past, you've described obicetrapib is serving the 50 to 150 range without competing with injectables relegated to the higher-risk established disease patients. So I guess how do the various Horizon outcomes, success, a near-miss, a failure each play out for them?

I think a total miss is unlikely because it did get 2 interims yes. So let's assume it's the next scenario, which is that it doesn't reach the p-value on the primary endpoint that people are hoping for, which if it's not it's not 20% or greater, it may not be statistically significant. It might be a P-value that's below -- not below 0.05, let's put them that way. Again, I think that's a scenario. But there are other scenarios where then it becomes, okay, let's look about the study itself. I mean there could be relatively high dropouts. It is an ASO. It has a lot of skin reactions. And we've -- so let's say -- once you look at on treatment or those that took the drug, it become significant. We can look at how much the lower you got and then model that for benefit. So there are ways that the study, even though may not be successful as a regulatory approval, trial could give us validation at LPA lowering has a benefit. So that would be a best-case scenario for us in our situate hope not. I hope it's a positive trial. As a clinician, I can tell you in my lipid clinic, I see patients 4 days a month or to Chicago, I would say 3/4 of them are high away patients want something to take for their LPA they're bad family histories, they're worried about it. So I think I think it would be most important to get this drug out there as soon as possible for those patients. With that said, though, it will be relegated to those that have LPWAs above roughly 150 nanomoles per liter in existing heart disease. So it would not be available for those below 150, we still have high risk down to 50 and/or they don't get a heart disease. And so it's also going to be very expensive, I believe, they'll be pricing it pretty high in that biologic range probably. Because it's -- that's how they design the high-risk group to get the high absolute benefit for the trial. And so we become the first Lp(a) lowering drug out there not technically by indication, but by benefit that people will be aware of that lower supply in that 50 to 150 range, quite effectively by about 50%. So stands, unfortunately, they do help the lower LDL, which makes a difference, but they don't know -- they actually raise Lp(A). So opacentripib becomes the really go-to drug for anybody with high LPLA in those that 50 to 150 which represents the majority of patients that have out there. So we see high official is a real upside for us in the marketplace.

Okay. Maybe in the last couple of minutes, let's talk about Alzheimer's. Michael, you plan to announce a new Phase IIb at the July AIC meeting?

It could be August, early August, yes.

Okay. So presenting 4 new studies based on Broadway biomarker data. no, no, no you're right. We are presenting posters at the meeting, our Investor Day obviously, we're announcing the. Okay, I'm sorry. Okay. Yes, we are -- we have 4 studies. So I guess talk to us about the design, the target population, time line and how could earlied expand.

So a great question. I think -- so we use a lot of AI technology in our data. We have a very rich data set. We have 1,500-plus patients on obicetrapib for a year. And so we already announced that in the APOE4 patients, especially the 44 homozygous, we got a benefit across the board on p-tau217 and also on other biomarkers. NfL, GFAP, Ptau 181, amyloid, all the biomarkers improved in the homozygous patients significantly, which was kind of unprecedented, especially NFL, which doesn't seem to be benefited by the anti-amyloid therapies. So that was quite exciting. But then using AI technology, we found that we have enriched the study for those that have a mildly elevated Ptau 217 and have either 4, 4, 3, 4, even 3, 3 that are older, they also benefit from obicetrapib. So if you think about Alzheimer's, 4, 4s get it in their 70s, 3, 4 get it in their 80s and 33 is getting their 90 days. So in our study, we found that all 4,4 benefited. So we think starting at age 55 is a good starting point. For 3/4, 60, 65, they start benefiting -- and then over 75 for 33, they start benefiting. So we think we found -- again, it makes a lot of biologic sense that we're trying to treat 20 years before there's cognitive impairment symptoms. Then we found that obicetrapib was benefiting these patients based on those risk markers and using Ptau as a great biomarker for amyloid in the brain that we're seeing this prevention of amyloid accumulation over that 12 months quite significantly across those 3 types of patient populations. So we're studying -- we've been doing a 3-cohort 400-patient trial with those 3 cohorts, 4, 4, 3, 4s and 3, 3s, having those other enrichment criteria to show what we can do in a prevention model for Alzheimer's. Again, where we're really benefited by the fact that the Ptau 217 keeps getting validated over and over again as an excellent biomarker for both prediction of progression and benefit in the trials, but also that the disease is being redefined now. Everyone's Alzheimer's used to say, that was dementia. Now they realize Alzheimer's is targeting 20 years ahead of any cognitive impairment. So they want to start treating Alzheimer's 20 years earlier now. And we hope that makes a big difference. And if you're in the lipid world like I am, we realized if we use the LDL lowering to treat heart failure, we never would have succeeded with LDL lowering we had to treat LDL lowering before there was heart damage to get the greatest benefit.

We're certainly looking forward to seeing how those trials progress. Best of luck to you, Michael. to you so much for being with us. A very comprehensive discussion. Really appreciate.

Thank you.