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

**Peter Attia** (0:11)
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 peterattiamd.com/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 Obesetropib. 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 Obesetropib 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 Obesetropib, and why they were designed, what they were designed to measure, the drugs' effect on the major lipid biomarkers, including Lp-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 patients? 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 reportings 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 Obacetrapib. Now this is a drug that's primarily being investigated because of its ability to reduce LDL cholesterol, and with it, APO-B. And I'm gonna talk about that as part of the story, but more broadly, I wanna talk about this drug in the spirit of cautious optimism as it pertains to Alzheimer's disease. So, here's why it's interesting. Opacetropib is a CETP 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 gonna 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 APOE44 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 Obesetrapib 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 CTEP 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. 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 CTEP 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 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 APO-B class and there's an APO-A1 class. The APO-B class is the one you've heard me talk about a ton, because those APO-B 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 a V6 to a V1 in size. They spend a tiny, tiny fraction of time as IDLs, 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 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 VLDLs, and therefore, you're going to, in 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 has simply been viewed as HDLs returning cholesterol molecules from the body to the liver. And so 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, for example, plaques in the coronary arteries, 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 Sterol Receptor Binding 1, 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 acids. So that's a cholesterol ester and cholesterol are cousins. It 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% of it. So 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 CTEP 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 CTEP 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 CTEP mediates an 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 CTEP activity is high, more cholesterol esters 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, 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 CTAB 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 CTEP is activated. And so what happens if you inhibit CTEP, 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 CTEP 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 Kastelan, 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 obesetrapib 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. This was literally 20 years ago. And as I got 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 deciliter. 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 would 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 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 CTEP 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 this is 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 dalsetrapib, which is a Roche drug. This raised HDL cholesterol by 30 to 40 percent, but it didn't really meaningfully lower LDL or APO-B. 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 APO-B 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 in 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 evacetrapib. 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 Lp little a, 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 APO-B 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 APO-B 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 Anicetrapib, 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 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 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 banger effect. And we've got to remember when this is happening. This is happening as the PCSK9 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 CTEP 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 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 mean, I'm totally making this up in 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 Obacetrapib. So these C-type 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 Obacetrapib, 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 Obacetrapib. And I think the argument was, look, the failure of these four CTEP inhibitors could be traced to issues, right? Which is basically two issues. Either they had off-target toxicity, again in the case of Torcetrapib'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 Obacetrapib is they went through 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 two trial, known as the ROSE trial, Obacetrapib was added to 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 APO-B reduction of 30%. When you looked at another trial called the OCEAN trial, also a phase two trial, the drug was combined with 10 milligrams of azetamide. It reduced LDL by 52%.