Conference Transcript - NAMS 2026-06-09

Operator

New Amsterdam. Very pleased to have you. Michael, welcome. Can I give you the opportunity to maybe just, you know, level set us and make some opening

Michael Davidson, CEO

framing remarks on the company? Sure. Thanks. Thanks, everyone, for being here. We've had a really productive year, you know, firing on all cylinders. I mean, 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, you know, based on a number of factors, we can go into more detail, but that interim analysis will start the actual point at the end of this year, and the readout will be in the first quarter of next year.

Operator

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

Michael Davidson, CEO

Well, you set an 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 before the DSMB, and then they have a charter which guides them on whether we hit the criteria for stopping the trial at that point.

Operator

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, you know, the framing again. How did you weigh getting to market potentially a year earlier versus the risk of potentially also jeopardizing the trial?

Michael Davidson, CEO

Well, 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 three LDL trials at the same time. So Brooklyn, Broadway, Tandem, and Prevail all started at the same time. 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 three 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 Broadway to be a mini-Prevail, and in fact, for the first time, and a lot of companies have copied this since, 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, well over 100 events at one year. And we saw this 21% relative risk reduction of our new four-point mace. We also had decided that Broadway would be informative on the final design of Prevail because we had initial four-point mace that a lot of companies had to use, which was urgent revask, cardiovascular death, non-fatal MI, and total stroke. And that's used, in fact, Horizon's 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 four-point MACE that was now being used in more recent trials, like Clear Outcomes, Fourier, and so forth. It's also the CTTC definition of four-point MACE that's being used for all the meta-analysis of all the LDL trials. That was also where the 0.79 hazard ratio was present. So we made the decision, we announced that a year ago, that we were going to change our four-point MACE to that four-point MACE. So Broadway was very informative on letting us know So that was the four-point mace that was recognized as now the new appropriate four-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 four-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 a study not for 20% relative risk reduction, 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, four-point MACE. Zetamide being 9%, and Repatha, and Aliracumab, and Evolacumab, Repatha, and Praliline at 15%. So we felt that 15% be powered would strengthen the trial significantly. but with that requirement to go to 15% power, we knew because we were limited by patient numbers, we were already fully enrolled, we had to go longer. So we're going to go longer. We also have more events now because the four-point MACE that included total revask instead of urgent also gave us about 20% more events. So we put in the new event rates, the new four-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 in your 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 rates 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 the P values that we selected, which are important for regulatory approval for both three-point and four-point MACE. And that would get us back on track for that timing of finishing the trial in the first quarter of 27. But that's a long answer to your question.

Operator

No, it's actually a great answer because I want to stay with event rates, believe it or not, for a second because, you know, you've stated that the blinded event rates are dropping in years two and three even more than the expected placebo decay. So I guess what gives you confidence that this is being driven by Obisetrapib's benefit rather than the placebo outperformance or changes in the standard of care? And maybe also just, you know, 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.

Michael Davidson, CEO

Yeah, so like I said, we looked at the first-year event rates with Prevail, and they matched almost exactly the Broadway one-year event rates across the board, three-point mace, four-point mace, death, non-fatal amai. All the events, all the composite events matched very closely to Prevail. So we felt that, again, kind of guide to what would happen historically, you know, 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 you'd expect from a decay over these multiple trials. Again, 14 trials, we can measure the predicted decay, and the famous line, for us at least, is a good way to lower your risk of heart disease would be a placebo in a cardiovascular outcome trial. I mean, so obviously that's an issue that 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, drop-outs, add-on GLP-1s or SLT-2s or PCSK-9s, 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 Obacetrapib is validating the 21% relative risk reduction we saw in the Broadway study itself. We also look at 14 different trials for all CVOTs of recent vintage. And again, we know the decay rates. We also know that our event rates, especially when you adjust for our risk, because we designed for Avail to be a high-risk population, LDL is over 100. All patients have ASCVD. 50% have diabetes. So you look at SELECT, for example, LDL was, and we know we're lower than trials that are done in a contemporary time, but 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 two-shots-on-goal approach. 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 we knew that would take an extra year, even though we modified the four-point mace because the event rates were 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 one year ahead of schedule.

Operator

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

Michael Davidson, CEO

Right, right. Well, so, again, the four-point MACE was driven by two reasons. One is Broadway was as good as urgent and elective were the same hazard ratio. Again, Clear Outcomes and Versilius are all both using total revast. They saw no difference in urgent versus total. And so that to us was kind of a simple reason to go with the total revask as opposed to urgent. So that made a lot of sense. And then, again, the CTTC definition also revealed, which is the incentive for trial, used total revask. So that gave us, again, a guidance there on that. That to us was a pretty easy decision. And also, just keep in mind that the big studies recently done, one's called CURGE, one's called Ischemia, in my field as a 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 revask is becoming much more evidence-based decisions. Like instead of seeing a lesion and dilating it, you've got to have symptoms. You have to have new onset of symptoms or symptoms that are getting more severe before you get a stent put in. Even payers are demanding more validation of medical necessity. So the blurring between elective and urgent is much less than it used to be 10 years ago.

Operator

And then I guess on the MACE 3 requirement, you know, 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, you know, year event decline is coming from the three-point components, which is, you know, non-fatal MI, stroke, HP death?

Michael Davidson, CEO

So that's actually a really good, that is our own, again, our own conservative thinking on the three-point has to hit also because even though the primary endpoint is four-point MACE, in Europe in particular, regulators like to see three-point MACE positive. So we would hate to have a situation where the four-point hit and the three-point did not. And that would have, 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 four-point but did not hit on three-point, then your regulatory certainty is in question. So you want to hit on both. And so we felt that if we're going to do an interim analysis, it would be easier not to have three-point in there to stop the trial. But for us, that would be an unfortunate situation if four-point hit and three-point did not. So we want to make sure three-point hits as well. Now, the threshold for three-point hitting is not as much as the four-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 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 three-point and we stopped for that reason, we would have regretted that decision. So we want to make sure that both four-point and three-point hit at the interim to stop the trial.

Operator

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%. You know, why would you believe that to be true from a commercial perspective?

Michael Davidson, CEO

Well, that's just what all the data tells us. One thing I want to make also a point, I forgot, you asked about it, was the three-point MACE reduction that we're seeing in, we're seeing all events going down, but in particular the three-point MACE.

Operator

Okay.

Michael Davidson, CEO

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 a, 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 is the study is positive or not. Like, for example, the new guideline just came out. They rank repatha, pralent, and bepidoic acid, Nexplitol, as the drugs they go to because they have outcome benefits. They don't talk about the relative risk reduction of those drugs. So they just have evidence-based benefit. So for most doctors, they don't even know. In fact, when you ask them, actually, what was the relative risk reduction, 90-plus percent get it wrong. I mean, they don't know what it is. It doesn't affect utilization as much as you think it would. Another example is Wagovi has select 20% relative risk reduction. Terseparatide has no benefit on outcomes. people are using terseparatide a lot more than WAGOVI. So it's just an example of these outcome studies. I guess in the academic world, what they are is potentially important, but in the real world it doesn't matter that much. And so we feel that the biggest reason why commercial uptake will go gangbusters with Obacetrapib is because the LDL-plus, positive benefit on outcomes. That checks the box. But the LPA lowering, the diabetes reduction, small particles, the Alzheimer's benefit in broad way that we saw, that's going to really drive uptake. And our data shows that strongly, that we get increased uptake for those other LDL plus benefits compared to other LDL drugs, including the oral PCSK9s in the market.

Operator

And that's a great segue, Michael, to, you know, just talking about the commercial landscape or even the competitive landscape, if you will, right? You've got the Merck oral PCSK9 launch potentially before the end of this year in Lysitide. You've got AstraZeneca's oral PCSK9 combo strategies across their CVRM portfolio. You framed sort of these entrants as wind in our sails, you know, rather than competitive threats. What evidence supports the market doubling beyond the 30 million patients not at goal?

Michael Davidson, CEO

Well, now the number is a lot bigger because of the new guidelines. It went down to 55. So it's a much bigger number. That really makes a huge difference on the numbers. You know, it's probably, it could be as much as double that. And so lower is better is the key, especially with LPL-A lowering if that is validated. And Horizon doesn't have to be positive in its own right. It could be something that's in between, which could even be better for us. I mean, something that showed a benefit that's more enhanced when you have an on-treatment analysis or things like that. I mean, Horizon has, it's on the borderline of where it's going to achieve statistical significance based on the powering and so forth. Again, they powered it for 20%. I mean, so, again, we want to, but the, when you have a drug that lowers LPL-A more than the oral PCSK9s, you have a drug that reduces risk of diabetes, not increase the risk, which is in the labels for the PCSK9 inhibitors to some degree, even though I don't think it's a real issue. The diabetes and the Alzheimer's benefit, we think the Alzheimer's benefit is getting a lot of traction with all the KOLs out there because they know that 8.4 is a lipid gene, and the prevention data with PTAL, the strengthening of the benefit of PTAL-217 being highly correlated with amyloid on PET, and that's highly correlated with progression to Alzheimer's, that's a great message. We're going to validate that with an upcoming study called Spinoza, and we're going to validate that. So I think all that together gives you a highly motivated reasons to use Obacetrapib over any other aldolorean drug. And, of course, the biggest issue in my mind is the safety and tolerability, ease of use. That really drives wide utilization, especially by primary care doctors. And primary care doctors loved ezetimibe before the whole enhanced issue blew up, you know, the benefit. Now it's growing again. It's going again. But what's easy about ezetimibe was it was so well-tolerated and safe, even though the 15% LDL lowering wasn't. But they rather get somebody that's very well-tolerated and safe as opposed to anything that has any side effects or has challenging use. And so we feel that's where Obacentropia really excels in that regard.

Operator

And then I guess on the regulatory strategy and the filing timeline, you filed in Europe, which I want to talk about. I guess just maybe just staying with that, what are the updated timelines in that region?

Michael Davidson, CEO

So, yeah, we filed in Europe. We should have approval this year for Germany and the U.K. Everything's going well on the regulatory side there. And then we'll be launching across Europe with our partner, Menorini, across many of these different countries.

Operator

And I guess, you know, because you're in the situation where your partner in Europe is going to be launching a drug before you launch in the U.S., so, you know, explain to us in the world of MFN, how does that affect the pricing architecture as you launch in all of these different markets in Europe?

Michael Davidson, CEO

Well, I don't want to comment specifically, but we are working close with Menorini on how best to go about the commercialization pricing strategy. But we've got Steve Albers, who ran Access at Nova Nordisk as our Access Public Affairs lead, and he's a fantastic expert in this area. what we're working with Manarini on are there are ways to structure pricing that gets us closer to the U.S. pricing. Across the range of countries? Well, it depends on the country, of course. And you remember, there's a very complicated system in Europe, but there are commercialization agreements. There are confidential pricing. So Europe is trying to adapt to the MFN world. But By the way, we here recently, and you may know as well, if not better than us, but we feel that anything law-wise, codification is unlikely to happen. On MFN. On MFN, yes.

Operator

So the industry is very opposed to it. Yeah, right, right, right. So you're saying this could just, even if there is something that emerges out of that, this is something that could eventually expire in three years.

Michael Davidson, CEO

Right, or just, you know, we feel that we have a lot of good arguments. We have no control over pricing in Europe. We have arguments that we could make about why that wouldn't affect us, but nevertheless, we are working closely with Menorini on how best to approach the pricing in Europe.

Operator

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

Michael Davidson, CEO

Potentially, we're talking with the FDA, And we're actually blessed at the FDA with the same team we've had for five years. And how are those discussions going? They're 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 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.

Operator

Okay. Let's talk a little bit about LP little A and Horizon. You touched on this briefly. Michael, you and I have had some conversations about this in the past. You've described Obetetrapib as serving the 50 to 150 LP little A range without competing with injectables relegated to the higher risk established disease patients. So I guess how do the various Horizon outcomes, success, a nail-miss, a failure, each play out for them.

Michael Davidson, CEO

I think a total miss is unlikely because it did pass two interims. Yeah, 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 20% or greater, it may not be statistically significant. It might be a p-value that's not below 0.05, let's put it 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. There could be relatively high dropouts. It is an ASO. It has a lot of skin reactions. So once you look at on-treatment or those that took the drug, it becomes significant. You can look at how much LPA lowering you got and then model that for benefit. So there are ways that the study, even though it may not be successful as a regulatory approval trial, could give us validation that LPA lowering has a benefit. So that would be a best-case scenario for us in our situation. I hope not. I hope it's a positive trial. As a clinician, I can tell you in my lipid clinic, I see patients four days a month at University of Chicago. I would say three-quarters of them are high-LPLA patients want something to take for their LPLA. They have bad family histories. They're worried about it. So I think it would be most important to get this drug out there as soon as possible for those patients. But that said, though, it will be relegated to those that have LTVAs above roughly 150 animals per liter and existing heart disease. So it would not be available for those below 150 who still have high risk down to 50 and or they don't yet have 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 that's how they design the high-risk group to get the high absolute benefit for the trial. And so we become the first LPLA-lowering drug out there, not technically by indication, but by benefit that people will be aware of, that lowers LPLA in that 50 to 150 range quite effectively by about 50%. So STADs, unfortunately, they do help. They lower LDL, which makes a difference, but they actually raise LPLA. So Obacentropia becomes the really go-to drug for anybody with high LPL-A in that 50 to 150, which represents the majority of patients that have LPL-A. We see high LPL-A as a real upside for us in the marketplace.

Operator

Maybe in the last couple of minutes, let's talk about Alzheimer's. Michael, you plan to announce a new Phase 2B at the July IC meeting?

Michael Davidson, CEO

It's going to be August, early August, yeah.

Operator

Okay, so I'm presenting four new studies based on Broadway biomarker data.

Michael Davidson, CEO

Oh, no, no, no, you're right. We are presenting four posters at the meeting. Our investor day is in August. We're announcing that the Spinoza start. Okay, I'm sorry. Okay, yeah, we have four studies.

Operator

So I guess talk to us about the design, the target population, timeline, and how could early intervention expand.

Michael Davidson, CEO

Right, right. So a great, 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 ovacetrapib for a year. And so we already announced that in the APOE4 patients, especially the 4-4 homozygotes, we got a benefit across the board on PTAL 217 and also on other biomarkers, NFL, GFAP, PTAL-181, amyloid, all the biomarkers improved in the homozygote patients significantly, which was kind of unprecedented, especially NFL, which doesn't seem to be benefited by any of the anti-amyloid therapies. So that was quite exciting. But then using AI technology, we found that if we enriched the study for those that have a mildly elevated P-TAL 217 and have either 4-4, 3-4, even 3-3 that are older, they also benefit from Obacetrapib. So think about Alzheimer's. 4-4s get it in their 70s, 3-4s get it in their 80s, and 3-3s get it in their 90s. So in our study, we found that all 4-4s benefited. So we think starting at age 55 is a good starting point. For 3, 4s, 60, 65, they start benefiting. And then over 75 for 3, 3s, 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 Obacetropia was benefiting these patients based on those risk markers and using PTAL as a great biomarker for amyloid in the brain, that we're seeing this prevention of amyloid accumulation over that 12 months, you know, quite significantly across those three types of patient population. So what we're studying, we'll be doing a three-cohort, 400-patient trial with those three cohorts, four-fours, three-fours, and three-threes, having those other enrichment criteria to show what we can do in a prevention model for Alzheimer's. Again, we were really benefited by the fact that the PTAL 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. Alzheimer's used to say that was dementia. Now they realize Alzheimer's is starting 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 used 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

Operator

benefit. Well, we're certainly looking forward to seeing how those trials progress. Best of luck to you, Michael. Thank you so much for being with us. Very comprehensive discussion. Really appreciate your kind of conversation. Thank you.