Thanks, everyone, for joining us for the last session of today. We're really happy to have New Amsterdam Pharma with us, represented by their CEO, Michael, and their CFO, Ian. So, thanks for being here.
Thank you, Leo.
Thank you, Leo. Thank you.
To start off, you know, maybe we'll just jump right into it. You know, obicetrapib is not the first type of CETP inhibitor, and the class has had a bit of a storied history. Maybe you can just talk about how obicetrapib is different to the historical agents before it and why you think mechanistically it should have a high likelihood of success.
Sure. So, well, first of all, it's a much more potent CETP inhibitor. You know, 10 mg, which is our dose in phase III, is far more potent than like 500 mg of evacetrapib, another CETP inhibitor that was also in the phase III. And it's more potent because it, it's able to bind to the CETP pocket, where the transfer, you know, activity is happening, results in much greater inhibition. So it was designed specifically for being the most potent CETP inhibitor and more, and more likely mimic the, you know, the total loss of function humans that we know live longer in Japan. And they didn't really consider, you know, at the initial CETP inhibitors, it was all about HDL raising.
When they got HDL raising of 50%, 30% to 75%, they were fine with that and stopped. What's different about obicetrapib is because it has a lot more potent CETP inhibition, results in much more profound LDL lowering, LDL cholesterol lowering, which is now linked to the why this target is beneficial in reducing cardiovascular disease.
That makes sense. So I guess across the phase II studies, you've shown about 40% LDL lowering there, about a little over that. And I guess as we think about the next upcoming catalyst, BROOKLYN and BROADWAY, I guess, what are you looking for from Brooklyn and Broadway? Are you looking to just kinda check the box of, you know, greater than 40%, or is there, you know, anything more specific you'd like to see coming out of those studies?
I think the key thing is, you know, validating the LDL efficacy across phase II. We did a pooled analysis, 42.6% LS mean reduction. And of course, the drug was very well tolerated and safe. And so, with Brooklyn and Broadway, it's, you know, two factors. One is, it's 12 weeks is the primary, but 12 months is the longer-term duration, the FDA requirement for durability of an LDL-lowering drug. So both efficacy and durability over 12 months are important endpoints. The other big thing, of course, is the safety, and safety can be basically general tolerability, which we can say with high confidence, we have a very well-tolerated drug. We have very little dropouts.
You know, people aren't stopping the drug for GI side effects or rashes or, you know, really any reason. We're seeing extremely low dropouts from the trial due to side effects, so that's really encouraging. The most important kind of safety factor to rule out is blood pressure increase because that was the torcetrapib issue. And we knew that already from phase II. In fact, we know from all the other CETP inhibitors, once torcetrapib factors are ruled out, these drugs are very safe. You know, they don't raise blood pressure. They had, you know, very good tolerability, excellent safety, so we need to rule out a blood pressure issue. So again, no effect on blood pressure in phase II, and then blinded phase III.
In this 2:1 randomization, we see no effect on blinded blood pressure levels across, you know, the full 12 months of the trial so far. So we feel those are the two important readouts, both the initial efficacy on LDL, hopefully exceeding 40%, then the long-term durability of that to week 52 or 12 months, and then overall safety. Once we have that type of information, I guess the most important study is gonna be BROADWAY, which is very similar to our PREVAIL outcome study. And once we have, you know, good efficacy and safety and LDL lowering, you can pretty much model the LDL lowering efficacy, and BROADWAY should translate to LDL lowering in PREVAIL, which then should translate into predictable cardiovascular outcomes based on, you know, 8 other mechanisms of LDL lowering, showing a very similar benefit.
Got it, and-
I'll just add, if you don't mind, Leo. I'll put in a plug for our R&D day, which is coming up on Thursday. And I think, you know, one of the things we're excited about is just the different aspects of Obi, right? Obi is not just simply an LDL-lowering drug, and I think our phase III studies will help us illustrate that point. And we have, as Michael mentioned, seen fairly consistent benefit from an LDL standpoint, but there are other risk factors that the obicetrapib does attenuate. So when you think about ApoB, Lp(a), and there's also potential for when you look at the class of CETP inhibitors that have been through the clinic, and here's where we are a beneficiary.
There's well over 60,000 patient-years of data available on CETP inhibitors, and we know them to be quite safe. Torcetrapib is the one exception because of an off-target side effect. But on top of that, the CETP inhibitors have consistently shown a diabetes benefit in terms of reduction in new-onset diabetes. So there's just a wealth of data we'll generate that goes well beyond LDL, which we'll be able to share with you as we complete the phase III trials.
Yeah, and definitely want to touch on that more. But I wanted to follow up on sort of the, the BROOKLYN and BROADWAY experience. I guess... How translatable historically have phase II trials been into the phase III setting? I guess, are there risks to the fact that now that you're dosing obicetrapib for longer, that perhaps you won't see the same magnitude of LDL reduction?
I mean, the risk is very low because when you see all, all the other, LDL trials, you know, statins, PCSK9 inhibitors, bile acid resins, even CETP inhibitors like, anacetrapib, evacetrapib. Well, once you lower the LDL in, in that 12-week period of time, the benefit is sustained across the entire several years, actually, for anacetrapib in the REVEAL trial. So there's no, there's no tachyphylaxis, we call it, of, of LDL lowering. And so the, the, the 12-week and the 52-week are basically identical. So we, we don't feel any concern about that, when it comes to the drug itself. Though there are-- There probably, you know, there's more dropouts and more drop-ins, but, but those are, again, we're very, really, knock on wood, we're very pleased with our metrics and our studies.
We're seeing very little of that. And so we should see a very, very small difference, if any, between our 12-week endpoint and our, our 52-week endpoint on, on LDL lowering.
Got it. And then to circle back to your point on the, the broad potential benefits of, of obicetrapib. I guess, you know, how important are those to actually, you know, quantify, to be able to bring physicians? Is this something, you know, and we'll get to the PREVAIL study. Is this something you, you'd hope you'd be able to teach physicians to, or is this more sort of a, a broader picture? And I guess, to what extent is it important to actually show Lp(a) reduction, show decreased risk of, of diabetes, to maybe, you know, deliver greater benefits ultimately in a study like PREVAIL?
Michael has a very unique perspective because he still sees patients. Yeah. So yeah, I still see patients four days a month at University of Chicago. In between, they're talking to investors or board meetings, whatever, I'm seeing patients, so it's a busy day. But I have this perspective that, you know, when you. Right now, I would say a third of my new referrals are patients self-referred for high Lp(a). It's a very important issue for patients. And I say, "Well, your LDL is 180. Why don't you worry. We should worry about your LDL first." It makes us, well, you know, that Lp(a), though, is what drove them to get in to see me. So it's very important for patients.
I think doctors are starting to get it also, of course, the ones that are knowledgeable. And so having a drug that can lower Lp by, let's say, 40% and also lower LDL, it becomes the go-to therapy for those patients that, that have high Lp. Now, that we have, as you're aware, many, at least 4 different Lp lowering therapies moving into phase III or later, very soon to re-report out outcome data next year. And so once that's available, those will be, obviously, the go-to therapies for those that have very high Lp, which, you know, the minimum, I think, or the level to get in is about 80 mg /dL or around 125 nmol/L . So we, with obicetrapib , could, we could take the rest of that high-level Lp that, that doesn't...
That's not, that's the ninetieth percentile. So between the elevated fiftieth percentile and the ninetieth percentile, there's a lot of people in that range where high Lp is going to be an issue, and they want something to address it, and having obicetrapib, well-tolerated, and having the effects in LDL as well, will be, I think, very well received. As Ian mentioned, the diabetes benefit, I have a lot of patients who say, "I don't want to take a statin because it raises the risk of diabetes." And in the latest data, it was 36% on high-intensity statins. It's not trivial, and a lot of patients are aware of it, and then clinicians are aware of it as well. So that attribute is going to be also well-received.
And then the last point I would say is the small dense LDL particle reduction of 90%, because when you're on a statin and you need. You're on a statin, and you measure the residual risk, but what the leftover is the particles that are small and dense with a CETP inhibitor, like obicetrapib, we should lower it by 90%. And so those, those all address that residual risk that we talk about when someone's on a statin and still has high risk for cardiovascular events. So this, this is an ideal drug combined with statins. And then, and it's not just another LDL-lowering therapy, it's, it's the overall profile of the drug, safety, tolerability, LDL efficacy, but also these other attributes, is going to make the big difference, for clinicians.
All right. I want to talk about PREVAIL, which is the cardiovascular outcome study. I guess you recently noted that you've expanded and well, over-enrolled the study, 9,500 patients. I guess, can you walk us through, sort of how you've enrolled the study to maximize risk factors, that you can have the largest benefit? And then remind us what the study is powered for and perhaps any benefit from the over-enrollment that you might see.
Sure. Well, the REVEAL trial was the anacetrapib 30,000-patient trial, and the biggest issue for that trial was it worked. It showed a 9% relative risk reduction with an 11 mg /dL drop in LDL. The baseline LDL was 61. So that was 30,000 patients, and it included patients with chronic atherosclerotic cardiovascular disease. This was a big study, and if you look at the top tertile, those that had LDLs above 70, there was a 17% relative risk reduction, with a 22 mg /dL drop in LDL. And that actually was more than expected, even though, even though it only lowered LDL by 22 mg /dL . That's the same absolute LDL lowering and CLEAR Outcomes, which saw a 13% relative risk reduction. So we wanted to try to maximize it.
So then who, who did the best in that trial? Obviously, those that had higher baseline LDLs, those that had high triglycerides, low HDL, high Lp(a), or diabetes. So we designed PREVAIL to try to match that, the upper tertile of REVEAL. So we have higher baseline LDL, or LDLs is over 100. The and risk enhancers were, as I described, a high triglyceride, low HDL, high Lp(a), diabetes, and other risk enhancers where the anacetrapib showed a greater benefit. So we also, other trials showed us that heart failure, if you take out heart failure, your risk, your risk reduction goes up quite a bit as well. Like in the ODYSSEY OUTCOMES and in FOURIER, it was 15% overall. If you took out heart failure, it went to 23%.
So, we think that you and that if you take out the patients that don't benefit, you also enhance your relative risk reduction. The last kind of thing that we wanted to focus on is duration, because REVEAL also showed us that you don't separate the lines until after two years. But you're talking about a very low baseline LDLs, they might separate faster with higher baseline, but nevertheless, we added a two-and-a-half-year minimum follow-up, which is the longest minimum follow-up ever in a chronic trial for LDL lowering. Two-and-a-half-year minimum. So we just finished enrollment, so it'll be at least four and a half years long. We had two years to get to this point, to enroll, now two and a half year minimum follow-up. So we have a long duration.
That 2.5 years should translate into a greater relative risk reduction. Another example, in FOURIER, which was the Repatha, a very similar population, it was a 2.3-year total duration. If they took patients that were on the drug for just a year, the relative risk reduction went from an overall 15% up to 20%. So all those factors, we believe, enrich PREVAIL with the right patients and the right design to maximize relative risk reduction. And we hope these other attributes, like small LDL particles, Lp(a) lowering, diabetes benefit, you know, could translate into greater outcomes. We'll have to see. I mean, most importantly, we want to try to achieve that greater than 15% relative risk reduction, which is what other LDL trials have shown in the last decade or less.
We want to at least achieve that as an outcome. But we think we can do better, the way our study's been set up and designed, and it's powered for that type of relative risk reduction.
Got it. And I guess on the regulatory path, it sounds like you're waiting for the outcomes trial before going to the FDA and filing this. I guess, can you talk about, you know, the combination of FDA discussions that led to that strategy, maybe your internal work about how to best approach the market that suggests that you won't be filing on BROOKLYN and BROADWAY?
Well, one correction, we will file on BROOKLYN and BROADWAY, but we're not going to file until we know the outcomes study is going to complete during the PDUFA period. So we wanna wait and kind of track events, and we can, once we know the events trajectory, when the full enrollment, so roughly a year from now, which is when we have the, basically, the filing ready for BROOKLYN and BROADWAY in tandem, our fixed-dose combination, we wanna file everything at the same time. So we go meet with the FDA, you know, Type C meeting, and then, assuming everything looks good, we go to a pre-NDA meeting.
So we're talking about a modest delay in filing, but we're meeting with the FDA, which wants to see the outcome study, you know, prior to approval. So we have that in our plans to have that data in the public domain at the time of approval. So the FDA has always approved drug without outcome data for LDL. LDL alone is one of the approvable surrogates without outcome data. But we think it's very important because, because of the class history, I think we have good explanations for everything, but because of the class history, we wanna make sure that no one has any hesitancy or concerns about using this drug when it's first approval.
And we wanna maximize success right off the bat with a drug like this, because having that outcome data in hand is gonna make a difference.
So one question we've been hearing, or concern we've been hearing from some cardiologists, and it's great that I have a cardiologist on stage that I can run this by, is that, there's been some meta-analysis that maybe CETP inhibitors produce HDL that might not be as functional, and that by administering a CETP inhibitor, though you're lowering the LDL, you're also making the HDL protective effect potentially less functional. I guess, do you see that as a concern? Do you think that's something to be worried about with this molecular mechanism or not so much?
Well, well, well, first of all, we did a lot of work on HDL functionality, and there's no, there's no impairment of functionality, by all the measures you can use. It actually works even better than without the drug on board. See, the HDL functionality is improved. So that is not true in regards to functionality. But we also have a lot more data about this from the other CETP inhibitors. And most importantly, again, it's anacetrapib with REVEAL, that in the subset of patients who had the highest baseline ApoA-I or HDL, the drug actually worked better. So those patients would have much higher HDLs on treatment. And if you look at evacetrapib, there was a total mortality reduction overall in this trial.
So if there was HDL dysfunction, you would not expect to see either greater benefits in those who had the highest HDL or even lower mortality when people got the drug. And so, that was an old thinking, you know, back when we first studied CETP inhibitors, HDL becoming dysfunctional. But all the evidence since then has been actually to the contrary, just the opposite, that the HDL raising is beneficial, and leads to other outcome benefits, and particularly, it's the diabetes benefit that we believe is HDL linked. Because HDL does remove toxic sterols from beta cells and improves survival of beta cells. That's, we believe that's the mechanism.
But also HDL, we believe, does a similar thing in the brain and helps remove toxic sterols cholesterol from the brain, and we showed that. We showed that 24-hydroxycholesterol and 27-hydroxycholesterol, which are linked causally with dementia and pathology. Inflammation of dementia is reduced for the first time with obicetrapib. So that is showing clearly that we can affect these toxic sterols and remove them from tissues where they could have adverse effects, like the brain or the beta cells. Now, that's an HDL-mediated effect. So we think, we think it's just the opposite, just the opposite, is that the HDL is highly functional, and, and having higher HDL may not, it may not be a MACE benefit, which is, which is, you know, clear from the, you know, from the trials done so far.
But yet, we believe it certainly could have other health benefits that we are evaluating.
Maybe just speaking to it from an adverse event standpoint. So if you look at our phase II data, and you've seen the pooled safety data there, there was no difference between obicetrapib and placebo. If you look at the data from the CETP inhibitors, and Michael mentioned anacetrapib in the REVEAL study, that's six years of follow-up, 30,000 patients. There was no such imbalance either.
Right. Yeah. No cancer, nothing. No, it's not. I think people just need to look at the data. It's just not. There's no signal of any harm. So, certainly no signal of harm. We still believe there's actually benefits of that HDL raising that we're trying to determine with our studies.
I know it's early days, and a lot of work before we get to this stage, but I'm curious if we can talk a little bit about sort of market positioning and how you see obicetrapib potentially fitting in. I guess, when the drug launches, I guess, do you see it being used first as preferred add-on to statins, maybe being used initially in the patients who are intolerant to statins, replacing PCSK9s? I guess maybe all of the above at once. But I guess, how do you see the market evolving? How do you see, you know, yourself as a physician first trying the drug, using it before you start using it more and more broadly?
Right, right. I think I might have a unique perspective, being a leading writer of branded lipid drugs and a CEO of a biotech company developing a novel lipid drug. I would say that perspective tells... I see the hurdles that most doctors have when they're trying to write another add-on to a statin or replace a statin if they can't take a statin. We think there are options out there, but they're really limited by... If they're oral, they only have two options, ezetimibe and Nexletol, Nexlizet, and they're both very modestly effective. For most patients, this is not gonna get you there to where you need to be, and this, you just don't get excited about using a drug that has that minimal LDL-lowering effects.
So you tend to shy, and I still use them a lot, actually, because I still think lower is better. So I'm one of the leading writers of Nexletol, Nexlizet in my area, as I am for Repatha and so forth. So I'm a very high decile writer of lipid drugs. But the... For most doctors, it's just not enough of an effect to get them excited. Now, for the injectables, it's more that they can't have the resources to help them with the training and the prior authorizations, so it's kind of just don't bother. And so I think for the first time, we're going to be able to supply a drug that can be very effective, especially the fixed-dose combination. You're talking about LDL lowering, maybe 60%. We'll have to see what...
So we saw that in our ROSE2 trial. So you just have one drug added to their statin, and they're done. Or if they can't take a statin, replace your statin, and they're done. Because once we use Nexletol, Nexlizet, which is for people who can't tolerate statins, but it's only a 15%-20% alone or 36% when you use ezetimibe. It's, for most patients, it's not enough efficacy to get them to where they should be. So you want to start with a drug that can just get them there, one single approach, and you're done with your therapy. That's the key message.
But ultimately, when it comes down to, you know, when you think of that overall profile, what it can do for other aspects, Lp(a), small particles, diabetes, that, that's when you get a tremendous enthusiasm. Even the HDL raising itself, again, we don't, we don't want to emphasize any MACE benefit with that, but other benefits that we want to try to highlight in our trials with that is something that we need to continue to develop with this unique drug. It will get doctors really excited about this option, and for the first time, we do have a very easy oral add-on, well-tolerated, that you can just write a prescription for, give them a bottle of samples, and you're done.
That, to me, is what's needed for a drug like an indication like this, where you want something very simple, well-tolerated, and accessible for patients.
I know we got probably half a second left, but I want to squeeze in one more, just around IP life and patent strategy. I guess, can you talk about, you know, your confidence in the strength of, of the patent life for obicetrapib?
Clearly, we're very confident. As you know, the composition of matter patent does expire in 2027 in the U.S., 2025 in Europe. We do have a second-generation patent, which is specifically the selection of a low dose of CETP inhibitor, specifically obicetrapib. So that selection patent takes our IP estate all the way to 2038, 2039. This is a patent that's been issued in over 35 countries. It's a patent strategy that's, you know, well, upheld well in terms of potential challenges. On top of that, there are additional patents that we have filed, including a new patent that we filed last year, which has the potential to issue at some point this year, and that's a new composition of matter patent.
So if that issues, then it takes our IP all the way to 2043.
Got it. Well, thank you so much for your time.
Thanks.
Really appreciated having you here. I think that concludes our session and the conference for today.
Thank you very much.