The Peter Attia Drive - #384 - Special episode — Obicetrapib: The CETP inhibitor with cardiovascular benefits and potential Alzheimer's prevention

Episode Date: March 16, 2026

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this special episode, Peter takes a deep dive into obicetrapib, an investigational drug that has captured his attention and renewed interest in an entire class of therapies known as CETP inhibitors. He explains what obicetrapib is and how it works, revisits the history of CETP inhibitors and why earlier versions of these drugs failed—sometimes dramatically—and breaks down the key clinical trials designed to evaluate their impact on cardiovascular risk. Peter examines how obicetrapib influences major lipid biomarkers, including LDL cholesterol and lipoprotein(a) [Lp(a)], and discusses emerging evidence from a study that explored the drug's effects on Alzheimer's-related blood biomarkers. He also highlights intriguing findings in individuals carrying the APOE4 allele and reflects on what these early results may mean for both cardiovascular disease prevention and potential implications for Alzheimer's risk, as well as how he is thinking about this therapy in the context of caring for his own patients. We discuss: Introducing obicetrapib: CETP inhibitor history, lipid biology, and early Alzheimer's biomarker signals in APOE4 carriers [2:15]; CETP biology explained: lipoproteins, reverse cholesterol transport, and how CETP inhibition alters HDL and LDL particles [5:15]; The early CETP inhibitor story: why raising HDL cholesterol alone failed to deliver cardiovascular protection [13:45]; The rise and fall of early CETP inhibitors: torcetrapib, dalcetrapib, evacetrapib, and anacetrapib [18:30]; Why obicetrapib may succeed where earlier CETP inhibitors failed [23:30]; The BROADWAY trial: obicetrapib's effects on LDL, ApoB, Lp(a), and residual cardiovascular risk [26:00]; Brain lipid metabolism and APOE4: how CETP inhibition may influence cholesterol transport in Alzheimer's disease [30:45]; Findings from the substudy of the BROADWAY trial which looked at changes in biomarkers of Alzheimer's disease [40:00]; Interpreting the BROADWAY Alzheimer's biomarker results: limitations, cautious optimism, and the need for a dedicated prevention trial [46:45]; Why Peter is optimistic about obicetrapib: cardiovascular benefits, Lp(a) reduction, and the path toward approval [50:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure

members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia-md.com forward slash subscribe. Welcome to a special episode of the drive. In this episode, I take a slightly different approach, where I'm going to walk you through a single topic in depth, breaking down the science behind. In this case, a drug that caught my attention and has me very excited.

The drug is called Obesetrapib. So I'm going to explain what it is, why it's generating renewed interest in cardiovascular medicine, at least as a class of drug, and why the emerging data may also have implications for Alzheimer's disease, particularly for those who carry an E4 allele. So in this episode, I'm going to discuss what Obesetrapib is, how it works as a class of drug called a CETP inhibitor.

The history of these drugs and why the previous versions of them have failed. And in some cases, spectacularly, the key clinical trials behind Obesetripyb and why they were designed, what they were designed to measure. The drugs affect on the major lipid biomarkers, including L.P. Little A, all very interesting. A study called the Broadway biomarker study and its findings in Alzheimer's-related blood biomarkers, again, including a very interesting subgroup in APOE carriers. And I guess most of all what these results mean, how do they have me thinking about this drug for my patient? So without further delay, I hope you enjoy this special episode of The Drive. So if you spend any time

thinking about Alzheimer's disease research, you get pretty familiar with the emotional whiplash that accompanies it. You know, one week you're going to see a biomarker. that moves and people talk about it and you'll see reporting all over the sort of lay press. And then the next week, some trial misses and the whole idea gets dismissed. And I think that's understandable for reasons maybe beyond the scope of what I want to talk about today. And I think it's also really true in the cases of prevention because prevention trials are hard to conduct. They take a long time. They're very expensive. And early signals can look compelling even before something's actually proven. So with that as background, today I'd like to talk

about a drug called Obesetrapib. Now, this is a drug that's primarily being investigated because of its ability to reduce LDL cholesterol and with it APOB. And I'm going to talk about that as part of the story. But more broadly, I want to talk about this drug in the spirit of cautious optimism as it pertains to Alzheimer's disease. So here's why it's interesting. Obisetrapib is a CET or CTEP inhibitor, which is a class of drug with a very complicated and quite honestly a very fascinating history in cardiovascular disease medicine. I'm going to actually talk about this in detail because I think it's important to the story. But in a recent large phase three lipid trial, there was a pre-specified biomarker study that looked at Alzheimer's related blood biomarkers

for a period of about 12 months. And in these studies, or in this study rather, the investigators saw an attenuation of P-Tau-217 progression with a very strong signal in the APO-E-4-4 individuals. So this combination, which is basically a revived drug, a drug that there's lots of examples of this class of drug in the graveyard, plus a coherent biomarker movement coupled with real genotype specificity is in my mind what makes this a very exciting topic that I want to kind of share with you all today. So to set expectations, I'm not going to come away from this proving that Obesetripyb prevents Alzheimer's disease or delays even cognitive benefits. But I will say that I haven't been as excited about any drug in the market or a drug that's about to enter the market as I am with

respect to this drug. So what do I want to accomplish here today? First, I want to kind of revisit the story of CETEP inhibitors, why so many of them have failed. I want to explain why maybe this drug is not failing, explain why lipid biology intersects with Alzheimer's disease, especially in the E4 carriers. I want to walk through the very specific study that is leading me to have this optimism. It's called the Broadway study. And I want to talk about what I hope happens next so that we can figure out whether this needs to be a part of everybody's life who's at risk. So to start, let's get into CETP or CETB biology. Now, to understand why this class of drug works, you have to understand something called reverse cholesterol

transport. And to understand how reverse cholesterol transport works, you kind of got to go back and understand lipoproteins. So apologies in advance for those of you that are already completely up to speed on lipoproteins, but I just want to make sure everybody's playing on the same level. Now, the way I talk about this with my patients is the way I'm going to kind of talk about it with you, which is to say that there are broadly speaking two classes of lipoproteins. Let's not forget why we have lipoproteins. Lipoproteins exist so that we can move cholesterol through our bloodstream. Why is that important?

Well, there's several factors. The first is every cell in the body needs cholesterol. It's a vital ingredient for our existence. If we didn't make cholesterol, we wouldn't actually be alive. And not every cell can necessarily make enough at every moment in time. So while every cell can make it, cholesterol needs to be shared across the body. Now, the problem with cholesterol is it is not. not water soluble. So the fancy word for that is it is hydrophobic. And so something that is

hydrophobic or something that repels water can't be transmitted through the blood because the blood is water. Our blood is plasma and a bunch of proteins. So the body has to come up with a slick way to do this. Again, the body has no trouble transporting things that are water soluble, right? So proteins, electrolytes, ions, these things move easily through the blood. Glucose, for that matter, right, just doesn't need anything to carry it. Not the same for cholesterol. So we evolved these cool things called lipoproteins, which as the name suggests are part lipid, part protein. The lipid or cholesterol fits on the inside, so it's shielded from the hydrophilic exterior, and the proteins are on the outside, which is what allows it to transmit through the blood. Now, you can broadly

divide these into two classes. There's an APOB class, and there's an APOA1 class. The APO B class is the one you've heard me talk about a ton because those APOB lipoproteins are the ones that cause atherosclerosis. Now, they're mostly LDLs. But we shouldn't forget how they start. They start out as VLDLs, very low density lipoproteins, which are big, really big. And they show up in all sorts of sizes. They cascade from, you know, a V6 to a V1 in size. They spend a tiny, tiny fraction of time as IDL's intermediate density lipoproteins before ultimately maturing as LDLs or low density lipoproteins. And so if you did a blood test, you might look at the cholesterol concentration of these. You would never be able to catch an IDL, but you would

certainly catch the VLDL cholesterol. And that level might be, you know, 15 to 20, maybe as high as 30 milligrams per deciliter. And then you would look at the LDL cholesterol and you would see a much bigger number. Now, remember, the LDLs are actually smaller, but you have so many more of them than the DLs and therefore you're going to an aggregate find much more cholesterol per unit volume of plasma. Now on the other side of the ledger, we have these things called HDLs or high density lipoproteins and they're structurally different. They come from a different lineage and they have a different lipoprotein that wraps around them and that lipoprotein is called APOA1. This is going to be important as we get into our story. So what is reverse cholesterol transport? Well, historically,

it is simply been viewed as HDL's returning cholesterol molecules from the body to the liver. And so, you know, if you asked me 10 years ago to tell you what RCT or reverse cholesterol transport was, that's what I would have said. I would have said it's when HDLs take, they delipidate, you know, for example, plaques in the coronary arteries, and they'll, or they take a sort of cholesterol out of other tissues and they bring it back to the liver. But I think we would now want to more technically refer to that term as HDL or APOA1 mediated trafficking of cholesterol. And again, that process is when a peripheral cell exports excess free cholesterol to that

protein, the APOA1 protein that forms the HDL particle, that cholesterol is then packaged into a more stable form carried with the HDL particle returns back. Okay. Now, the direct RCT or reverse cholesterol transport is when the HDL delivers that cholesterol straight into the liver, sometimes the intestine, and it unloads it there via a receptor called the sterile receptor binding one or SRB1. I only mention that because I'm going to bring it up later. I don't actually care if you remember that. But just remember that HDLs can take cholesterol directly to the liver and they deliver it through that receptor. But there's also something called indirect RCT. I don't think I even learned what indirect RCT was until maybe eight or nine years ago,

which is not to say it wasn't understood before then. I'm just telling you I didn't understand this before then. And here is where this is actually kind of cool. The HDL doesn't deliver the cholesterol itself. Instead, it exchanges its cholesterol ester, which are the cholesterol molecules bound to long chain fatty acid. So that's a cholesterol ester and cholesterol are cousins. and exchanges those things for the triglycerides inside the APOB particle, which is usually the LDL. So let's just go back and say that again. So you got an HDL that's full of cholesterol ester. It bumps into an LDL in the periphery, which has got a bunch of triglycerides in it.

They swap triglyceride for cholesterol ester. And then those LDL particles, quote unquote bad guys, do a good thing. they take cholesterol back to the liver. Now, it's important to understand that an enormous amount of reverse cholesterol transport takes place via this route, some 40 to 50 percent of it. So, you know, it's important to understand that LDLs aren't all bad. They are doing this one good thing. Now, I know what you're thinking. If we lower our LDLs, does that mean we get less reverse cholesterol transport? No, the direct pathway just picks up the balance. But it's just an interesting thing to observe here. Okay. Now, what does all this thing have to do with CTEP? Well, what does CETEP stand for?

I said it, I think, at the beginning. It stands for cholesterol ester transfer protein. And so at a high level, you can think of the CETEP as a molecular shuttle that exchanges the cholesterol ester in the HDL for the triglyceride molecule in the LDL as part of this indirect reverse cholesterol transport pathway. Now, because CETAP mediates in exchange of cholesterol ester from HDL for triglyceride in the APOB containing particles, it doesn't just move cholesterol. It actually reshapes the particles themselves. And so when C-TEP activity is high, more cholesterol esters enter, pardon me, leave the HDL and move into the LDL. So HDL becomes cholesterol poor and triglyceride rich, while LDL becomes cholesterol rich and triglyceride poor. Okay. But remember,

Remember, while we like the idea of cholesterol going back to the liver, if you just load those LDLs of cholesterol, we know where they're ultimately going to end up. So this is not a condition we want. So the problem with too much CTAP activity is that the triglyceride-enriched HDL is unstable. It gets rapidly trimmed down by enzymes called lipases, both in the liver and at the endothelium, these produce smaller HDL particles that can either be rebuilt or cleared from circulation. But what happens is that you have those cholesterol-enriched LDL particles that will ultimately go back to the liver, but may not, right? They may also end up ending up in artery walls. So that's what's happening when CETEP is activated. And so what happens if you

inhibit C-TEP, the opposite happens. So less cholesterol ester leaves HDL. This results in much larger cholesterol-rich HDL particles. So HDL cholesterol, the biomarker, goes up, and LDL cholesterol, the biomarker, goes down. All right, so with that as background, I think we can now talk about what I think is a very fascinating history of this class of drug called CETP or CETEP inhibitors. Now, it's important to understand the context of this. So in the 90s, I think, around the 90s when this class of drug were first developed, the excitement was almost entirely around the HDL story. What do I mean by that? Well, the CTEP inhibitors, these first versions, which we'll talk about, dramatically raised HDL cholesterol, oftentimes doubling it. Okay. Now, at the time,

this term that still exists today, unfortunately, was even more prevalent, which was that HDL was good cholesterol. And so the thinking was really straightforward in its reductionist manner, which was if low HDL is bad, because it's associated with more cardiovascular risk, then raising HDL should be good. And therefore, giving a drug that raises HDL cholesterol is a good thing. And that was the rationale for going forward with this. Now, I discussed this in a podcast a couple of years ago with John Kastelin, and it turned out that that assumption was overly simplistic, although it wasn't known at the time. So since that time, Mendelian randomizations have been done and have actually failed to support the hypothesis that HDL cholesterol is causally linked to favorable cardiovascular

disease outcome. By the way, that's the exact opposite of what the Mendelian randomizations have showed us about LDL cholesterol. Every Mendelian randomization that has looked at the level of LDL cholesterol, again genetically controlled to a large extent, has found the opposite, that it is indeed causally related to bad outcomes. But we don't see that with HDL. I would like to think that if people knew that 30 years ago, it might have saved some of the pain that was coming our way, but at the same time, maybe we wouldn't have obisetrapid today. So I don't want to be too much of a revisionist on history. The point here is the Mendelian randomizations would suggest to us that simply raising HDL cholesterol is not going to reduce cardiovascular events by itself.

Another point that wasn't known at the time that is known today that's been reinforced by human genetics is that individuals who have a loss of function variance in CTEP have markedly elevated HDL cholesterol and in some analyses at least have lower cardiovascular disease risk, but that benefit appears to track with reductions in their non-HDL cholesterol, not with the increase in HDL cholesterol. In contrast, loss of function mutations in the HDL receptor SRB1, remember I talked about how when we were dealing with direct versus indirect reverse cholesterol transport, the direct route is what allows the HDL to take cholesterol straight to the liver or to the gut and transport it through the SRB1. So if you have a loss of function mutation in the

gene that codes for SRB1, what's going to happen? You're going to have a defective transporter. Your HDLs are not going to do a good job in getting cholesterol out of them into where they need to go. The HDL cholesterol is actually going to go up, isn't it? So those patients walk around with very high HDL cholesterol, and yet they have a higher increase in coronary artery disease risk. Just as an aside, a very, very close friend of mine who I've known for almost 20 years, has always had very high HDL cholesterol and low LDL cholesterol. And we used to always marvel at his lipid panels. You know, this was literally 20 years ago.

And as I got deeper, deeper, deeper, deeper into the weeds of this a few years ago, I said to him, hey, brother, I know your HDL cholesterol is 110 or 120 milligrams per deciliter, and your LDL cholesterol is 60 or 70 milligrams per decilator. And that almost assuredly portends a good outcome here. Do me a favor and just get a calcium score because I just want to, be sure you don't have one of these SRB1 mutations. And if you do, you would look exactly like you do, but you'd be riddled with heart disease. And unfortunately, that turned out to be the case. And so he did have a very aggressive finding on his calcium scan and had a lot of calcium

there. Fortunately, none of it was so far along that, you know, he's not going to be totally fine and he's now being treated and everything's going to be fine. But I point that out to just say, do not assume that because a person has high HDL cholesterol or low LDL cholesterol that they're necessarily safe. Okay. So all of this is to say that the biology here is super, super complicated. Okay, so let's now talk about the various C-TEP inhibitors. So the very first of these, which again, we talked about this on the podcast with John a few years ago, was Torsetrapib. And this is the one I talked about because I really remember this one well. This was a Pfizer drug. It was put into a study paired with a torvastatin, which was about to come off patent.

And everybody was excited because a torvastatin had all of its benefits that were demonstrated over and over again in lowering LDL cholesterol and lowering cardiovascular events. They then pair it with this drug, which doesn't just further lower LDL, but raises HDL. Everybody thinks there's going to be a home run. Drug gets stopped prematurely in 2006 because of increased mortality, which was secondary to it, raising blood pressure. Now, this turned out to be an off-target toxicity, meaning the drug was doing something that was raising blood pressure that had nothing to do with CTEP. And it's unfortunate for that drug and that company, but none of the CTEP inhibitors that have followed have suffered

that limitation. So fast forward about six years to dalsetripyb, which is a Roche drug. This raised HDL cholesterol by 30 to 40 percent, but it didn't really meaningfully lower LBL or APOB. and not surprisingly then, given what we know today, which is it's not the rise of HDL that matters, it's the fall of LDL or RAPOB that matters. This didn't move the needle and the drug was abandoned. So it just didn't, you know, it looked like it had favorable findings and biomarkers, but there were no good outcomes, no bad outcomes, no safety side effects, but the drug was pulled by Roche in 2012.

Fast forward a little bit more to evesetripyb. this was a drug that Eli Lilly was working with. This had a much bigger effect on HDL. It was increasing it by over 100 percent, so more than doubling HDL cholesterol. LDL cholesterol was falling by about 30 percent, APOB falling by about 15 percent, and even LPLA, which I'm going to talk about in a minute, declined by about 20 percent. But ultimately that trial was terminated after a median follow-up of just about two years. And in retrospect, when you looked at all of the data, it seems that the initial belief of the LDL reduction was probably overstated. Whereas when you looked at the relevant metric of APOB reduction, it was about

12 milligrams per deciliter, probably not big enough to move the needle over two years. Now, a 12 milligram per deciliter reduction in APOB over the course of your lifetime, of course would move the needle, but not over a couple of years. So they did another study that also failed to find a benefit and then Lilly pulled the drug on that drug in 2015. That was followed up by another study called Reveal. In this drug, in this trial, Merck was looking at a drug called Anacetrapib and it was adding it to a torvastatin therapy to reduce coronary events. This study, I believe, did see a reduction in coronary events of. of nine or 10% over a median follow-up of about four years. And there was an extended follow-up

of another two years that demonstrated a further reduction of events to about 12% over about six years. And, you know, the magnitude of that benefit was consistent with what would be predicted from the degree of APOB lowering. So it was a modest effect. This was not kind of a bangor effect. And we've got to remember when this is happening. This is happening as the PCS-C-C-C-E inhibitors are coming online and these things are like blowing the doors off of these metrics. But here's what was important about this study is that it really was a proof of concept that C-TEP inhibitors could reduce cardiovascular events. They could lower APOB particles and they were largely risk-free if you didn't have these off-target effects. But because this drug had another

odd side effect, which is it was, it had a very long half-life and it was retained. in fat cells. Now, to be clear, no one was able to demonstrate that this posed a problem, but Merck decided to pull the plug. Now, I don't, I mean, I'm totally making this up and speculating. We all remember that Merck had what I consider one of the best drugs ever, Vioxx, and was probably too late to put a black box warning on that, which is what they should have done. Instead, they ultimately got called out, had to pull this drug off the market. To this day, many patients, myself included, resent that, and wish that, they had just put a black box warning on it. And so maybe they were a little bit gun-shy in this regard. But

nevertheless, that drug got yanked. So you go, what is that? Five drugs or four drugs that go O for four, or at least three of them go O for three and maybe the fourth one kind of hits, but has this weird issue of getting held up in fat cells and therefore they decide, forget it. We're not going to take that risk. And so all of that is prelude to where we are with Obisetrapib. So these C-TEP inhibitors clearly have a complicated history, and it begs the obvious question, right? Was what in the world would make the fifth shot-on goal, in this case Obesetrapib, any different? And I kind of remember that being my mindset when I interviewed John three years ago or whenever I interviewed John, who, by the way, is one of the founders of the company that makes Obesetrapib.

And I think the argument was, look, the failure of these four C-TEP inhibitors could be traced to issues, right? which is basically two issues. Either they had off-target toxicity, again, in the case of tortetripyb's blood pressure effects, or maybe even this fat accumulation issue, or because they just didn't lower LDL cholesterol and APOB enough despite raising HDL a lot. And so the hope with Obesetrapib as they went through, you know, the process of marching into phase one and phase two was, look, as long as it's not having off-target toxicity and as long as it's really producing a robust LDL response, this drug could be a banger. And so that's exactly what has shown to be the case. So in the phase true trial known as the Rose trial, Obesetriptib was added to high statin

or high intensity statin therapy and the drug produced reductions in LDL cholesterol that were enormous, an additional 50% reduction in LDL cholesterol on top of high statin therapy or high intensity statin therapy and an APOB reduction of 30%. When you looked at another trial called the Ocean Trial, also a Phase 2 trial, the drug was combined with 10 milligrams of azetamide. It reduced LDL by 52%. And when you looked at the Rose 2 trial where high-intensity statin and azetamib were combined with Obesetripyb, you saw a decrease in LDL of over 60%. All of this then feeds into the phase three trials, which are Broadway, which was looking at Obesetripyb on top of maximum lipid lowering therapy and Brooklyn, which was a trial done specifically in patients

with familial hypercholestrolemia or ph. On top of maximum tolerated lipid modifying therapies. So basically take those patients with ph who are very high risk, put them on whatever maximum cocktail of drugs you can put them on, and then at Obesetrapib. And then another study called Prevail, which was looking actually at cardiovascular outcomes in patients with existing cardiovascular disease. So three trials there to talk about, but the one I really want to talk about is Broadway. So Broadway enrolls 2,500 patients with established atherosclerotic disease or ph, familial hyperclostrolemia, who are already receiving maximum therapy. So why am I highlighting this study?

Because these are the two patients where you see the maximum amount of residual risk. What is residual risk? That's the risk that remains when you've controlled everything you can control. So in these patients, when 10 milligrams daily of Obesetripyb was added to background therapy, LDL cholesterol fell by an additional 30 percent, three months out compared to a 3 percent increase in the placebo group. So the placebo group was on maximum drugs, but nothing else. And over time, it just drifted up 3%, which is probably noise.

But what was not noise and was statistically significant was this 30 percent reduction in the OB group. ApoB, B, remember, it doesn't, it's not going to decline as much. much, it went down 16% compared to 1.8% placebo. The HDL cholesterol, for what it's worth, just going through this, went up by 125%, which was, you know, we always expect that with CETEP inhibition. And L.P. Little A fell by a third. I want to take a second to explain that, by the way, because that's super interesting. I won't give a full primer on L.P. Little A, but I know that people who listen to this podcast regularly are no stranger to what's going on there, which is to say LP little A is an independent and genetically determined cardiovascular risk factor

that's really difficult to modify. And it's surprisingly common, right? Anywhere from one in eight to one and 12 people are going to carry this risk. But the fact that a C-TEP inhibitor is reducing it by a third is pretty promising. So how do we think it's happening? Well, there's a number of possible mechanisms, but what it appears to be doing is decreasing the synthesis of apolyproproteen little a. So if you decrease the synthesis of apo little a, you're going to make less LP little A, which is made out of an LDL and an APO little A. Now, there's also some speculation that it increases the expression of hepatic HDL receptors, and it's proposed that those could be receptors for LP little A clearance. But I think that's speculation at the moment.

I would probably rather not comment on it too much further than to just observe the outcome. Now, there's one other thing that I think is worth kind of talking about here, and that is that across all of these CETP programs, there appears to be either kind of a neutral effect or even possibly a favorable effect on incident diabetes. Now, again, we're going to see more of that in Obesetrapid because we have more trials. And while I think it's too soon to say if these are definitive, they are notable because, as we've talked about in the past, statins are indeed associated with a small but real increase in the risk of type 2 diabetes. And so I just want to point out that if, in fact, this benefit is confirmed

of what we would call metabolic neutrality or even benefit, I think it tells us a couple of things. One, it says that the negative impact that statins have on insulin resistance are not necessarily a product of the reduction in cholesterol, and rather must be some other issue associated with the statins. We've talked about this elsewhere that it might have to do with the impact that statins have on the gut. But more importantly, I think it says that if we have a drug that is lowering LDLC and APOB and LP-L-A and L-P-L-L-A and its metabolized.

beneficial, boy, this is a drug that has a lot of potential benefits. So all of this is to say we've got a drug that lowers LDL, APOB, reduces LP-L-A, remodels HDL-L-P-L-A, remodels HDL particles, potentially, you know, at best, probably no adverse metabolic tradeoffs, maybe some benefits. And all of this is looking very promising. We are awaiting the results of the Prevail Phase 3 trial, which is a cardiovascular outcome study. So just a word on. the differences in approval in Europe where this drug has already been approved, or the data or at least are sufficient for approval, the drug should be on the market in Europe in Q4 of 26. Europe is able to approve drugs based on well-understood biomarkers, and this is clearly an example

of that. In the U.S., we will wait until hard outcomes are done. So until you see a mortality benefit or a mace reduction, major adverse cardiac event reduction, this will not be approved. So the US is going to lag by a couple of years here. Let's talk about what I really want to talk about. It's not that I didn't want to talk about all this stuff. I really did. But I want to now get into the part that is super exciting to me, which is brain biology and APOE.

So the brain is one of the most lipid, rich organs in the body. And of course, cholesterol is one of the most important structural components of neuronal membranes, synapses, and myelon. So without cholesterol, the brain is not going to function. But there's a catch, right? the brain lives behind a paywall. We call the blood brain barrier. It's not really a paywell, but I just wanted to say that. So the brain lives behind a blood brain barrier. And that blood brain barrier separates the brain's cholesterol economy from the rest of the body. So the lipoprotein

particles that we measure in the blood are essentially sequestered from the brain. And as such, the brain cannot rely on circulating cholesterol the way the liver can. Instead, the brain runs its own semi-independent lipid management system, which transports its own lipoproteins. Now, in the periphery and the rest of the body, outside of the blood-brain barrier, cholesterol balance depends on a very coordinated system of lipoprotein particles. We've talked about this, right? So we talked about the HDL particles, which are built around APOA1. They accept cholesterol from cells, transport back to the liver, sometimes give them to

LDLs that take them back to the liver. All of this stuff is going on. And I didn't even get into the rest of that stuff. We know that as the liver excretes bile, bile travels through the gut. The gut has another check in there where it gets to bring cholesterol in, determine if we need it or not. If not, we excrete it. If yes, we bring it back in.

There's like the body is really, really pretty marvelous when it comes to this. But the brain uses a very different set of proteins to mediate this. Now, instead of using APOA1, which is the protein on the HDL that is largely responsible for this accounting, its lipoproteins, the one in the brain, are organized around something called apolypo-protein E, or apoe-e. So astrocytes and microglia synthesize apo-e-containing particles that shuttle cholesterol and phospholipids to neurons. These particles support membrane repair and synaptic remodeling and basically the overall lipid homeostasis within the CNS. Now, the efficiency of that system, of course, turns out to be highly genotype dependent.

So most people carry two copies of an isoform for the gene that makes this protein called APOE3. So there are three isoforms, APOE2, APOE3, and APOE4. This is a bit of the problem with the nomenclature here. Whenever I'm talking about the gene, I'm talking about the all caps version. So capital A, capital P, capital O, capital E, and then the number, two, three, or four. You get two of those, two genes, one from mom, one from dad. So there are six possible combinations, right? 2-2, 2-3, 24, 3-3, 34, 4.

Each of those will yield a slightly different protein. The protein is called APO-E, no number, just APO-E, and it's no caps. So it's just little A, P-O-E, no caps. So that's how you know if you're thinking about the protein or thinking about the gene that codes for the protein. So if you look at the APOE protein that is made by two copies of the APOE3 gene, we call this the wild type, it handles cholesterol transport in the brain really well. But if you look at the protein, the APOE protein that is made by one or two copies of the APOE4 gene, it does not. So if you look at the protein made from one or two copies of an APOE4 gene, it's less efficiently lipidated. It interacts differently with transporters. And it forms lipoprotein particles that are less

structurally stable and less effective at moving cholesterol. And what's really amazing, by the way, as an aside, is all of this comes down to a single amino acid substitution. And for anybody who cares, it's a cysteine to an arginine substitution at position 112. And that, one little change alters the protein's shape and all of its downstream behaviors. And of course, this isn't unique here. If you look at something like sickle cell disease, it's the same sort of thing. It's one amino acid substitution that completely changes the way a red blood cell functions. In this case, you know, through hemoglobin. So why do we care? What we care? Because if cholesterol isn't properly transported, it's going to build up. And lipid droplets that form inside of

astrocytes and microglia, they cause problems, right? The membrane composition shifts, oxidative stress, because remember cholesterol is highly sensitive to oxidative stress. That's what's leading to atherosclerosis. It increases. Amyloid clearance becomes less efficient and inflammatory signals rise. And if that sounds like a bad thing, then you understand enough about Alzheimer's disease already, which is amyloid accumulates inflammation increases. And over a long enough period of time, often decades, this impaired ability to traffic lipids is what contributes to synaptic dysfunction and ultimately to neuronal death. So this is why APOE4 is a concern. If an individual has one or two copies of this gene, they are at an increased risk for Alzheimer's disease. Now, we also know

that this is not a deterministic gene. There are lots of people that are walking around with APOE4 genes that are doing just fine in advanced age. So I don't want to be sitting here. you're sending fear signals to those individuals. But we have to acknowledge that on average, statistically speaking, if you have one or two copies of that gene, you are basically getting sped up in your brain aging. And what that effectively means is if you have two copies of an APOE4 gene, your probability of developing clinically significant cognitive decline is going to be about two decades sooner than a person who's got two copies of an APOE3 gene. Again, that's on average. It's not for everybody. There are lots of things that can modify this. We've talked about

some of them. We've talked about clotho, KLVS. We've talked about all the lifestyle factors that can make a difference. But, you know, I just want to acknowledge the obvious here. Now, I think kind of at first glance, I think, you know, C-TEP inhibition might not really matter to this discussion because it operates in plasma, where it facilitates the exchange, as we talked about, between cholesterol ester, between the different particles of lipoproteins, right? The cholesterol esters that move between HDL and LDL. And this creates a larger HDL particle where APOA1 stays on longer and it's cleared more slowly. So again, APOA1 concentrations increase. That's why we see HDL cholesterol go up. So what does this have to do with the brain? Well, APOA1 stays.

APOA1 is a relatively small protein, and therefore small lipid poor HDL particles, which contain APOA1, can indeed cross the blood-brain barrier in limited amounts. So by increasing the circulating pool of APOA1, the CTEP inhibitors can increase the availability of functional APOA1 within the CNS. And so in the context of APOE for patients, where endogenous lipid transport is less efficient, a greater concentration of APOA1 could augment cholesterol e-flux and at least partially offset the impaired functioning APOE protein. Right? The APOE mediated trafficking of that protein. Now, in addition to that, of course, Obesetrapib confers all the usual. cerebral vascular benefits through the well-established antithorotic atherosclerotic actions by lowering APOB, et cetera.

In addition, functional HDL particles can carry lipophilic antioxidants as well and move them. So basically increasing HDL concentration, especially HDLs that are small but yet functional that can still get into the CNS may raise the antioxidant content within the circulating HDLs and to a limited extent within the CSF. So enhanced antioxidant availability could help attenuate the oxidative stress and lipid peroxidation process, which of course is also known to amplify neuroinflammatory signals. Now, again, this framework is somewhat speculative, but it is biologically coherent. It also offers a plausible explanation for why the most pronounced Biomarker effects in the Broadway sub-study, which I'm going to discuss here in a second,

are observed in the APOE4E4 individuals, because this is a group in whom lipid trafficking is the dysfunction of lipid trafficking, I should say, is the most noted. And therefore, this group in theory should benefit the most from everything I just said. Okay, so let me just go back to the study because I'm kind of getting ahead of myself in the spirit of trying to explain the biology. So let's go back to the Broadway study. So remember, this is the one where there was a pre-selected endpoint. So the investigators pre-selected a subset of this study to look at the biomarkers of Alzheimer's disease.

And the primary endpoint was a change in plasma phosphorylated tau-217, known as p-tow-217, over the period of 12 months, from baseline to a year out. They also looked at some secondary endpoints, which were changes in the ratio of ptow 217 to amyloid beta 42 to 40 ratio, and then ptow 181, something called glial fibulari acidic protein, or GFAP, and neurofilament light chain or NFL. I just want to point out that ptow 217 is probably the most important of these. At least we believe that today because it is the most highly correlated. with the findings that we see on a type of PET scan that is used to measure tau.

And that PET scan and its results tend to be the most highly correlated with the clinical outcomes that we see. So that's why they chose P-TOW 217 is the primary endpoint. The participants were stratified by their APO-E genotypes. Specifically, they looked at 3-3s, 3-4s, and 4-4s, and then all the related subgroups. Okay. So in the final biomarker analysis, there were over 1,500 participants, median age of 67, two-thirds of them are male. Now, these are patients without dementia or cognitive impairment, but they did have cardiovascular disease. It's always important to just remember what your patient population was. Let me spend one more second, just going over the biomarkers. So as I said,

plasma petal, probably the strongest predictor we have in the periphery that correlates with Alzheimer's Again, I mentioned why, right? Amyloid pet positivity and tau aggregation are probably the best thing we can do to predate clinical stage symptoms. AB 420 ratio reflects amyloid biology. So as AB42 becomes sequestered into plaque with the brain circulating AB 42 declines relative to 40, which lowers that ratio. If you look at Ptow 217 to that ratio, it just integrates these two. GFAP is a marker of astroglyle activation and NFL is a marker of axonal injury and neurodegeneration. It's not specific to Alzheimer's disease, by the way, but when levels are rising, it indicates neuronal damage. So if we take these things together and look at their results, what did we see?

So across all participants, Obisetripyb significantly attenuated the increase in Ptow-2-7. the primary outcome compared to placebo over 12 months. So if you take everybody, the adjusted mean percentage increase in the placebo group was 5%. So petal 217 went up by 5% across everyone in the study over a year and in the placebo group. And then the obestetripyb group, it only went up 2%. Now, what's interesting is if you start to look at the subgroups. So in the subgroups, if you look at the subgroups, if you look at the. just those that had an E4. So this was people who were E3, E4 or E4-E4, the difference is a little more stark.

In the placebo group, you saw an increase of Pita 217 by over 7%, whereas in the Obesetrapib group, it only went up about 1.5%. Now, what if you just looked at E3, E4, and E4-E4 in people over the age of 70? So again, what we're doing is we're taking that same population, but now we're looking at the people who are at even higher risk just based on age. And here we saw that in the placebo group, Ptow 217 over the course of a year rose by almost 15%, but it went up only by 6% in the Obesetrapib group. Again, that was statistically significant. But the most interesting finding for me, and I think anybody who would look at the paper, is what happened in the admittedly small subset, 29 people of E4E4s, of any age. In this population, the placebo group saw an increase of almost 13%, 12.7% of Pita 217 over the course of a year. And yet in the

group on Obesetrapib, they actually saw a reduction in Pita 217 by nearly 8%, creating a difference of over 20% between those treatment groups, and that was, again, highly statistically significant, despite the small number. So all of this is to say that something really interesting could be happening in these APO-E4 patients. Now, again, as I want to say, it's a very small subgroup, right? So this is a 1,500-person trial. 29 of those people were E-4-E-4. As a general rule in the population, E4E4 is about 2% of the population, but E3E4 is about 20 to 25% of the population. So there's still a lot of people out there who would benefit from this. We're just seeing an enormous impact in these people.

In the overall population, again, the effect size is statistically significant. We don't know if it's clinically significant. I won't go into all the other biomarkers just for the sake of time, but we're going to link to the study in the show notes so you can look and see all of the other biomarkers. But everything moved in the right direction. There was not a single biomarker for which Obesetrapib didn't do exactly what it would, what you would want it to do. This was true in Ptow 217.

This was true in NFL, GFAP. Of course, the impact was most notable and most significant in the E4E4. So there's one figure that you can look at where you see the effect on the E4E4s, and it's profound. So I'll go over that figure because I already gave you the Ptow 217 where you see a 20% difference between placebo and treatment. In the NFL, it's a 17% difference in the GFAP. It's a 15% difference in the Ptow 181. It's almost a 14% difference in the AB 42 to 40 ratio. It's about an 8% difference. And in the ratio of the ratio, the P tau to the AB 4240, it's almost a 23% difference. So how do we interpret this?

Well, let's be cautious here. Okay, so first and foremost, this is a biomarker study. It's not a cognitive outcomes trial. There were no formal cognitive tests that were included here. And we don't know for certain if these biomarker changes would translate into preserved cognition or a slower decline or, you know, reduced incidence of dementia. As I said, Ptow 217 is a very well-validated biomarker. So everything looks very optimistic, but without the outcome trial, we don't know. Second thing we don't know is this is a short study. It was only 12 months. Alzheimer's is a disease

that unfolds over decades. Do we know if we looked at over a long enough period of time, would this benefit be maintained? I already talked about the size of the subclass, very small group. Sometimes you can see extraordinarily results in small groups, and it's a bit of a weird statistical outlier, and we don't know what it's going to look like in a larger cohort. I think the last point I would make here is less of a knock, but it's just a, we don't know exactly why this is happening. Now, to be clear, we don't know why clotho works either, and yet we still think it's very exciting and interesting.

We don't know how clotho works. I mean, we don't even understand how clotho impacts its targets in the brain since it doesn't appear to cross the blood brain barrier. So all of that is to say, we know a bunch of things that Obesetrapibb does. We know that it modifies HDL and APOB, reduces LPD, LPD, reduces LPD, and reduces LB, But it's hard to say which of these are the ones that are contributing. And I personally find the HDL APOA1 story to be the most compelling argument here. So what can we conclude?

So I think we can say, look, this is a biomarker study that was internally coherent and very genotype specific. And I think it has very high biologic plausibility. I think we have to be cautious because biomarkers don't necessarily establish clinical benefit. We need more data, but I'm very excited. And I think personally that this signal is strong enough to justify a dedicated prospective prevention trial that should include cognitive outcomes, imaging, longer follow-ups, and frankly, larger genomic stratified groups.

Now, such a study would need to be enriched for APOE4 carriers. So we'd want lots of E3 and E4. So I'd want to, if I were designing that study, I'd want, you know, I'd want every E44 on the planet that I could get enrolled in that study, and I'd want basically two-thirds of the patients to be at least a three-four. In my mind, you want people who are completely cognitively intact in mid-life or slightly older. So these are probably people in their 60s, maybe 70s, but again, completely cognitively intact, no evidence of MCI. And you're going to need to track these people for quite a long period of time. So it's going

to have longitudinal cognitive endpoints that are going to be sensitive to early decline. It's going to have to have serial plasma biomarkers, maybe some imaging studies, including amyloid or tau pet, and it needs to run for several years. So look, I'm not suggesting that this is an easy thing to do. I'm just suggesting that if we lived in a parallel universe where resources were unlimited, that's the study that you would do to figure this out. So look, it's hard for me to mask my personal optimism around this. I love the biological plausibility of this. And I think that Obesetrapib has done something that its four predecessors has failed to do. And I think if it did nothing else but have the impact that I think it's going to have from a cardiovascular disease

standpoint, which is to say it's going to have a significant impact on LDLC and APOB. I believe it will likely show a reduction in events, certainly over a long enough period of time. The impact on LP L.A. is very interesting to me. And the fact that it is metabolically neutral or potentially positive is also very exciting. And then you layer this on as well. This is a drug I'm very excited about. And I look forward to learning more about the approval process in the United States. Again, I don't I don't know exactly where it is in that life cycle. But I know it'll probably still be a couple of years after the European approval, which will lead to the launch of this drug in the second half or last quarter of 2026.

So that'll wrap up our story on Obesetrapib. Hope you guys found that as interesting as I did. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter Atia MD. You can also leave us review. on Apple Podcasts or whatever podcast player you use.

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