#384 - Special episode — Obicetrapib： The CETP inhibitor with cardiovascular benefits and potential Alzheimer's prevention
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Summary
Obacetrapib is a class of drug with a very complicated history in cardiovascular disease medicine. In this episode, I discuss what it is, how it works as a CETP inhibitor, the history of these drugs, and why the previous versions of them have failed, and in some cases spectacularly.
Transcript
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Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Atiyah. This podcast,
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Welcome to a special episode of The Drive. In this episode, I take a slightly different approach
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where I'm going to walk you through a single topic in depth, breaking down the science behind,
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in this case, a drug that caught my attention and has me very excited. The drug is called
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Obacetrapib. So I'm going to explain what it is, why it's generating renewed interest in
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cardiovascular medicine, at least as a class of drug, and why the emerging data may also have
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implications for Alzheimer's disease, particularly for those who carry an E4 allele. So in this
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episode, I'm going to discuss what Obacetrapib is, how it works as a class of drug called a CETP
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inhibitor, the history of these drugs, and why the previous versions of them have failed,
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and in some cases spectacularly, the key clinical trials behind Obacetrapib and why they were
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designed, what they were designed to measure, the drug's effect on the major lipid biomarkers,
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including LpA, all very interesting, a study called the Broadway Biomarker Study and its
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findings in Alzheimer's-related blood biomarkers, again, including a very interesting subgroup in
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APOE carriers. And I guess most of all what these results mean, how do they have me thinking about
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this drug for my patients. So without further delay, I hope you enjoy this special episode of
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The Drive. So if you spend any time thinking about Alzheimer's disease research, you get
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pretty familiar with the emotional whiplash that accompanies it. You know, one week you're going
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to see a biomarker that moves and people talk about it and you'll see reportings all over the
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sort of lay press. And then the next week, some trial misses and the whole idea gets dismissed.
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And I think that's understandable for reasons maybe beyond the scope of what I want to talk
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about today. And I think it's also really true in the cases of prevention because prevention
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trials are hard to conduct. They take a long time. They're very expensive. And early signals
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can look compelling even before something's actually proven. So with that as background,
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Today, I'd like to talk about a drug called Obacetrapib. Now, this is a drug that's primarily
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being investigated because of its ability to reduce LDL cholesterol and with it ApoB.
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And I'm going to talk about that as part of the story. But more broadly, I want to talk about
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this drug in the spirit of cautious optimism as it pertains to Alzheimer's disease. So here's
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why it's interesting. Obacetrapib is a CETP or CTEP inhibitor, which is a class of drug
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with a very complicated and quite honestly, a very fascinating history in cardiovascular
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disease medicine. I'm going to actually talk about this in detail because I think it's important to
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the story. But in a recent large phase three lipid trial, there was a pre-specified biomarker study
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that looked at Alzheimer's related blood biomarkers for a period of about 12 months.
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And in these studies, or in this study rather, the investigators saw an attenuation of P-tau-217
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progression with a very strong signal in the APOE44 individuals. So this combination,
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which is basically a revived drug, a drug that there's lots of examples of this class of drug
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in the graveyard, plus a coherent biomarker movement coupled with real genotype specificity
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is in my mind what makes this a very exciting topic that I want to kind of share with you all
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today. So to set expectations, I'm not going to come away from this proving that obocetripib
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prevents Alzheimer's disease or delays even cognitive benefits. But I will say that I haven't
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been as excited about any drug in the market or a drug that's about to enter the market as I am
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with respect to this drug. So what do I want to accomplish here today? First, I want to kind of
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revisit the story of CTEP inhibitors, why so many of them have failed. I want to explain why maybe
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this drug is not failing, explain why lipid biology intersects with Alzheimer's disease,
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especially in the E4 carriers. I want to walk through the very specific study that is leading
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me to have this optimism. It's called the Broadway study. And I want to talk about what I hope happens
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next so that we can figure out whether this needs to be a part of everybody's life who's at risk.
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So to start, let's get into CETP or CTEP biology. Now to understand why this class of drug works,
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you have to understand something called reverse cholesterol transport. And to understand how
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reverse cholesterol transport works, you kind of got to go back and understand lipoproteins.
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So apologies in advance for those of you that are already completely up to speed on lipoproteins,
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but I just want to make sure everybody's playing on the same level. Now, the way I talk about this
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with my patients is the way I'm going to kind of talk about it with you, which is to say
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that there are broadly speaking two classes of lipoproteins. Let's not forget why we have
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lipoproteins. Lipoproteins exist so that we can move cholesterol through our bloodstream. Why is
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that important? Well, there's several factors. The first is every cell in the body needs cholesterol.
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It's a vital ingredient for our existence. If we didn't make cholesterol, we wouldn't actually be
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alive. And not every cell can necessarily make enough at every moment in time. So while every
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cell can make it, cholesterol needs to be shared across the body. Now, the problem with cholesterol
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is it is not water soluble. So the fancy word for that is it is hydrophobic. And so something that
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is hydrophobic or something that repels water can't be transmitted through the blood because
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the blood is water. Our blood is plasma and a bunch of proteins. So the body has to come up
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with a slick way to do this. Again, the body has no trouble transporting things that are
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water-soluble, right? So proteins, electrolytes, ions, these things move easily through the blood.
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Glucose, for that matter, right? Just doesn't need anything to carry it. Not the same for
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cholesterol. So we evolved these cool things called lipoproteins, which as the name suggests,
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are part lipid, part protein. The lipid or cholesterol fits on the inside, so it's shielded
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from the hydrophilic exterior, and the proteins are on the outside, which is what allows it to
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transmit through the blood. Now, you can broadly divide these into two classes. There's an ApoB
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class, and there's an ApoA1 class. The ApoB class is the one you've heard me talk about a ton,
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because those ApoB lipoproteins are the ones that cause atherosclerosis. Now, they're mostly LDLs,
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But we shouldn't forget how they start. They start out as VLDLs, very low-density lipoproteins,
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which are really big. And they show up in all sorts of sizes. They cascade from a V6 to a V1
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in size. They spend a tiny, tiny fraction of time as IDLs, intermediate-density lipoproteins,
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before ultimately maturing as LDLs, or low-density lipoproteins. And so if you did a blood test,
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you might look at the cholesterol concentration of these. You would never be able to catch an
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IDL, but you would certainly catch the VLDL cholesterol, and that level might be, you know,
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15 to 20, maybe as high as 30 milligrams per deciliter. And then you would look at the LDL
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cholesterol, and you would see a much bigger number. Now remember, the LDLs are actually
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smaller, but you have so many more of them than the VLDLs, and therefore you're going to, in
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aggregate, find much more cholesterol per unit volume of plasma. Now on the other side of the
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ledger, we have these things called HDLs, or high-density lipoproteins, and they're structurally
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different. They come from a different lineage, and they have a different lipoprotein that wraps
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around them, and that lipoprotein is called APOA1. This is going to be important as we get into our
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story. So what is reverse cholesterol transport? Well, historically, it has simply been viewed as
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HDLs returning cholesterol molecules from the body to the liver. And so, you know, if you asked
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me 10 years ago to tell you what RCT or reverse cholesterol transport was, that's what I would
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have said. I would have said it's when HDLs take, they delipidate, you know, for example,
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plaques in the coronary arteries and they'll, or they take a sort of cholesterol out of other
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tissues and they bring it back to the liver. But I think we would now want to more technically
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refer to that term as HDL or APOA1-mediated trafficking of cholesterol. And again, that
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process is when a peripheral cell exports excess free cholesterol to that protein, the APOA1
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protein that forms the HDL particle. That cholesterol is then packaged into a more stable
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form, carried with the HDL particle, returns back. Okay. Now, the direct RCT or reverse
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cholesterol transport is when the HDL delivers that cholesterol straight into the liver, sometimes
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the intestine, and it unloads it there via a receptor called the sterol receptor binding one
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or SRB1. I only mentioned that because I'm going to bring it up later. I don't actually care if
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you remember that, but just remember that HDLs can take cholesterol directly to the liver and
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they deliver it through that receptor. But there's also something called indirect RCT.
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I don't think I even learned what indirect RCT was until maybe eight or nine years ago,
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which is not to say it wasn't understood before then.
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I'm just telling you I didn't understand this before then.
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And here is where this is actually kind of cool.
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The HDL doesn't deliver the cholesterol itself.
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Instead, it exchanges its cholesterol ester, which are the cholesterol molecules bound
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So that's a cholesterol ester and cholesterol are cousins.
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and exchanges those things for the triglycerides inside the ApoB particle, which is usually the
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LDL. So let's just go back and say that again. So you got an HDL that's full of cholesterol
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ester. It bumps into an LDL in the periphery, which has got a bunch of triglycerides in it.
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They swap triglyceride for cholesterol ester. And then those LDL particles,
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quote-unquote bad guys, do a good thing. They take cholesterol back to the liver.
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Now, it's important to understand that an enormous amount of reverse cholesterol transport takes
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place via this route, some 40% to 50% of it. So, you know, it's important to understand that LDLs
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aren't all bad. They are doing this one good thing. Now, I know what you're thinking. If we
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lower our LDLs, does that mean we get less reverse cholesterol transport? No, the direct pathway
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just picks up the balance. But it's just an interesting thing to observe here. Okay, now what
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does all this thing have to do with CTEP? Well, what does CTEP stand for? I said it, I think,
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at the beginning. It stands for cholesterol ester transfer protein. And so at a high level,
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you can think of the CTEP as a molecular shuttle that exchanges the cholesterol ester in the HDL
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for the triglyceride molecule in the LDL as part of this indirect reverse cholesterol transport
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pathway. Now, because CTEP mediates an exchange of cholesterol ester from HDL for triglyceride
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in the ApoB-containing particles, it doesn't just move cholesterol, it actually reshapes
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the particles themselves. And so when CTEP activity is high, more cholesterol esters
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enter, pardon me, leave the HDL and move into the LDL. So HDL becomes cholesterol poor
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and triglyceride-rich, while LDL becomes cholesterol-rich and triglyceride-poor.
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Okay, but remember, while we like the idea of cholesterol going back to the liver, if you just
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load those LDLs of cholesterol, we know where they're ultimately going to end up. So this is
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not a condition we want. So the problem with too much CTAP activity is that the triglyceride-enriched
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HDL is unstable. It gets rapidly trimmed down by enzymes called lipases, both in the liver and at
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the endothelium. These produce smaller HDL particles that can either be rebuilt or cleared
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from circulation. But what happens is that you have those cholesterol-enriched LDL particles that
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will ultimately go back to the liver, but may not, right? They may also end up ending up in
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artery walls. So that's what's happening when CTEP is activated. And so what happens if you
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inhibit CTEP? The opposite happens. So less cholesterol ester leaves HDL. This results in
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much larger cholesterol-rich HDL particles. So HDL cholesterol, the biomarker, goes up,
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and LDL cholesterol, the biomarker, goes down. All right. So with that as background, I think
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we can now talk about what I think is a very fascinating history of this class of drug called
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CETP or CTEP inhibitors. Now, it's important to understand the context of this. So in the 90s,
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I think around the 90s when this class of drug were first developed, the excitement was almost
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entirely around the HDL story. What do I mean by that? Well, the CTEP inhibitors, these first
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versions, which we'll talk about, dramatically raised HDL cholesterol, oftentimes doubling it.
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Okay. Now at the time, this term that still exists today, unfortunately, was even more prevalent,
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which was that HDL was good cholesterol. And so the thinking was really straightforward in its
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reductionist manner, which was if low HDL is bad because it's associated with more cardiovascular
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risk, then raising HDL should be good. And therefore, giving a drug that raises HDL
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cholesterol is a good thing. And that was the rationale for going forward with this.
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Now, I discussed this in a podcast a couple of years ago with John Kastelin, and it turned out
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that that assumption was overly simplistic, although it wasn't known at the time. So since
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that time, Mendelian randomizations have been done and have actually failed to support the
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hypothesis that HDL cholesterol is causally linked to favorable cardiovascular disease
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outcome. By the way, that's the exact opposite of what the Mendelian randomizations have showed us
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about LDL cholesterol. Every Mendelian randomization that has looked at the level of
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LDL cholesterol, again, genetically controlled to a large extent, has found the opposite,
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that it is indeed causally related to bad outcomes. But we don't see that with HDL.
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I would like to think that if people knew that 30 years ago, it might have saved some of the pain
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that was coming our way. But at the same time, maybe we wouldn't have Obisetrapib today. So
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I don't want to be too much of a revisionist on history. The point here is the Mendelian
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randomizations would suggest to us that simply raising HDL cholesterol is not going to reduce
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cardiovascular events by itself. Another point that wasn't known at the time that is known today
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that's been reinforced by human genetics is that individuals who have a loss of function
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variants in CTEP have markedly elevated HDL cholesterol and in some analyses at least have
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lower cardiovascular disease risk. But that benefit appears to track with reductions in
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their non-HDL cholesterol, not with the increase in HDL cholesterol. In contrast, loss of function
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mutations in the HDL receptor SRB1. Remember I talked about how when we were dealing with
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direct versus indirect reverse cholesterol transport, the direct route is what allows the
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HDL to take cholesterol straight to the liver or to the gut and transport it through the SRB1.
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So if you have a loss of function mutation in the gene that codes for SRB1, what's going to happen?
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You're going to have a defective transporter. Your HDLs are not going to do a good job in getting
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cholesterol out of them into where they need to go. The HDL cholesterol is actually going to go up,
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isn't it? So those patients walk around with very high HDL cholesterol, and yet they have a higher
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increase in coronary artery disease risk. Just as an aside, a very, very close friend of mine
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who I've known for almost 20 years, has always had very high HDL cholesterol and low LDL
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cholesterol. And we used to always marvel at his lipid panels. You know, this was literally 20
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years ago. And as I got deeper, deeper, deeper into the weeds of this a few years ago, I said
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to him, hey, brother, I know your HDL cholesterol is 110 or 120 milligrams per deciliter and your
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LDL cholesterol is 60 or 70 milligrams per deciliter. And that almost assuredly portends
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a good outcome here, do me a favor and just get a calcium score. Because I just want to be sure
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you don't have one of these SRB1 mutations. And if you do, you would look exactly like you do,
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but you'd be riddled with heart disease. And unfortunately, that turned out to be the case.
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And so he did have a very aggressive finding on his calcium scan and had a lot of calcium there.
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Fortunately, none of it was so far along that he's not going to be totally fine. And he's now
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being treated and everything's going to be fine. But I point that out to just say, do not assume
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that because a person has high HDL cholesterol or low LDL cholesterol that they're necessarily safe.
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Okay. So all of this is to say that the biology here is super, super complicated. Okay. So let's
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now talk about the various CTEP inhibitors. So the very first of these, which again, we talked
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about this on the podcast with John a few years ago, was torcetripib. And this is the one I talked
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about because I really remember this one well. This was a Pfizer drug. It was put into a study
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paired with atorvastatin, which was about to come off patent. And everybody was excited because
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atorvastatin had all of its benefits that were demonstrated over and over again in lowering
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LDL cholesterol and lowering cardiovascular events. They then pair it with this drug,
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which doesn't just further lower LDL, but raises HDL. Everybody thinks this is going to be a home
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run, drug gets stopped prematurely in 2006 because of increased mortality, which was secondary to it
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raising blood pressure. Now, this turned out to be an off-target toxicity, meaning the drug was
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doing something that was raising blood pressure that had nothing to do with CTEP. And it's
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unfortunate for that drug and that company, but none of the CTEP inhibitors that have followed
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have suffered that limitation. So fast forward about six years to dalsetripib, which is a Roche
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drug. This raised HDL cholesterol by 30 to 40%, but it didn't really meaningfully lower LDL or
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ApoB. And not surprisingly then, given what we know today, which is it's not the rise of HDL
00:19:44.960
that matters, it's the fall of LDL or ApoB that matters, this didn't move the needle and the drug
00:19:51.460
was abandoned. So it just didn't, you know, it looked like it had favorable findings in biomarkers,
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but there were no good outcomes, no bad outcomes, no safety side effects, but the drug was pulled
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by Roche in 2012. Fast forward a little bit more to evocetrapib. This was a drug that Eli Lilly
00:20:09.840
was working with. This had a much bigger effect on HDL. It was increasing it by over 100%,
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so more than doubling HDL cholesterol. LDL cholesterol was falling by about 30%,
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percent, ApoB falling by about 15 percent, and even LP little a, which I'm going to talk about
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in a minute, declined by about 20 percent. But ultimately, that trial was terminated after a
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median follow-up of just about two years. And in retrospect, when you looked at all of the data,
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it seems that the initial belief of the LDL reduction was probably overstated. Whereas when
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you looked at the relevant metric of ApoB reduction, it was about 12 milligrams per
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deciliter, probably not big enough to move the needle over two years. Now, a 12 milligram per
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deciliter reduction in ApoB over the course of your lifetime, of course, would move the needle,
00:21:01.660
but not over a couple of years. So they did another study that also failed to find a benefit,
00:21:08.120
and then Lilly pulled the drug on that drug in 2015. That was followed up by another study
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called Reveal. In this trial, Merck was looking at a drug called anacetrapib, and it was adding
00:21:25.580
it to atorvastatin therapy to reduce coronary events. This study, I believe, did see a reduction
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in coronary events of 9% or 10% over a median follow-up of about four years. And there was an
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extended follow-up of another two years that demonstrated a further reduction of events to
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about 12% over about six years. And, you know, the magnitude of that benefit was consistent with what
00:21:56.140
would be predicted from the degree of ApoB lowering. So it was a modest effect. This was
00:22:02.260
not kind of a banger effect. And we've got to remember when this is happening. This is happening
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as the PCSK9 inhibitors are coming online and these things are like blowing the doors off of
00:22:10.880
these metrics. But here's what was important about this study, is that it really was a proof
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of concept that CTEP inhibitors could reduce cardiovascular events, they could lower ApoB
00:22:22.680
particles, and they were largely risk-free if you didn't have these off-target effects.
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But because this drug had another odd side effect, which is it had a very long half-life and it was
00:22:36.340
retained in fat cells. Now, to be clear, no one was able to demonstrate that this posed a problem,
00:22:43.740
but Merck decided to pull the plug. Now, I mean, I'm totally making this up and speculating. We
00:22:50.100
all remember that Merck had what I consider one of the best drugs ever, Vioxx, and was probably
00:22:55.380
too late to put a black box warning on that, which is what they should have done. Instead,
00:22:59.680
they ultimately got called out, had to pull this drug off the market. To this day, many patients,
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myself included, resent that and wish that they had just put a black box warning on it. And so
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maybe they were a little bit gun-shy in this regard. But nevertheless, that drug got yanked.
00:23:13.540
So you go, what is that, five drugs or four drugs that go 0 for 4, or at least three of them go 0
00:23:21.360
for 3, and maybe the fourth one kind of hits, but has this weird issue of getting held up in fat
00:23:26.440
cells, and therefore they decide, forget it, we're not going to take that risk. And so all of that is
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prelude to where we are with Obacetrapib. So these CTEP inhibitors clearly have a complicated
00:23:38.440
history and it begs the obvious question, right? Was what in the world would make the fifth shot
00:23:42.960
on goal, in this case Obacetrapib, any different? And I kind of remember that being my mindset when
00:23:49.400
I interviewed John three years ago or whenever I interviewed John, who by the way is one of the
00:23:54.380
founders of the company that makes Obacetrapib. And I think the argument was, look, the failure
00:24:00.440
of these four CTEP inhibitors could be traced to issues, right? Which is basically two issues.
00:24:06.500
Either they had off-target toxicity, again, in the case of torcetripib's blood pressure effects,
00:24:11.320
or maybe even this fat accumulation issue, or because they just didn't lower LDL cholesterol
00:24:17.540
and ApoB enough despite raising HDL a lot. And so the hope with obacetripib as they went through,
00:24:24.580
you know, the process of marching into phase one and phase two was, look, as long as it's not
00:24:29.620
having off-target toxicity, and as long as it's really producing a robust LDL response,
00:24:34.440
this drug could be a banger. And so that's exactly what has shown to be the case. So in the phase
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true trial known as the ROSE trial, opacetrapid was added to high statin or high intensity statin
00:24:45.340
therapy, and the drug produced reductions in LDL cholesterol that were enormous. An additional
00:24:51.920
50% reduction in LDL cholesterol on top of high statin therapy or high intensity statin therapy,
00:24:57.320
and an ApoB reduction of 30%. When you looked at another trial called the OCEAN trial,
00:25:04.220
also a phase two trial, the drug was combined with 10 milligrams of ezetimibe. It reduced LDL
00:25:09.440
by 52%. And when you looked at the ROSE2 trial, where high intensity statin and ezetimibe were
00:25:19.220
combined with obacetripib, you saw a decrease in LDL of over 60%. All of this then feeds into the
00:25:27.140
phase three trials, which are Broadway, which was looking at obocetripib on top of maximum
00:25:33.280
lipid lowering therapy, and Brooklyn, which was a trial done specifically in patients with familial
00:25:40.040
hypercholesterolemia or FH on top of maximum tolerated lipid modifying therapies. So basically
00:25:45.820
take those patients with FH who are very high risk, put them on whatever maximum cocktail of
00:25:51.140
drugs you can put them on, and then add obocetripib. And then another study called Prevail,
00:25:56.440
which was looking actually at cardiovascular outcomes in patients with existing cardiovascular
00:26:01.320
disease. So three trials there to talk about, but the one I really want to talk about is
00:26:05.760
Broadway. So Broadway enrolls 2,500 patients with established atherosclerotic disease or FH,
00:26:13.020
familial hypercholesterolemia, who are already receiving maximum therapy.
00:26:16.840
So why am I highlighting this study? Because these are the two patients where you see the
00:26:21.180
maximum amount of residual risk. What is residual risk? That's the risk that remains when you've
00:26:25.860
controlled everything you can control. So in these patients, when 10 milligrams daily of
00:26:31.660
obocetripib was added to background therapy, LDL cholesterol fell by an additional 30%
00:26:38.640
three months out compared to a 3% increase in the placebo group. So the placebo group was on
00:26:44.340
maximum drugs, but nothing else. And over time, it just drifted up 3%, which is probably noise.
00:26:49.140
But what was not noise and was statistically significant was this 30% reduction in the OB
00:26:53.880
group. ApoB, remember, it's not going to decline as much. It went down 16% compared to 1.8% in
00:27:01.420
placebo. The HDL cholesterol, for what it's worth, just going through this, went up by 125%,
00:27:08.160
which we always expect that with CTEP inhibition. And LP little a fell by a third. I want to take
00:27:16.000
a second to explain that, by the way, because that's super interesting. I won't give a full
00:27:20.180
primer on LP little a, but I know that people who listen to this podcast regularly are no stranger
00:27:25.500
to what's going on there, which is to say LP little a is an independent and genetically determined
00:27:32.160
cardiovascular risk factor that's really difficult to modify. And it's surprisingly common, right?
00:27:38.060
Anywhere from one in eight to one in 12 people are going to carry this risk. But, you know,
00:27:42.840
the fact that a CTAP inhibitor is reducing it by a third is pretty promising. So how do we think
00:27:46.440
it's happening? Well, there's a number of possible mechanisms, but what it appears to be doing is
00:27:51.680
decreasing the synthesis of apolipoprotein little a. So if you decrease the synthesis of APO little
00:27:57.940
a, you're going to make less LP little a, which is made out of an LDL and an APO little a.
00:28:04.640
Now, there's also some speculation that it increases the expression of hepatic HDL receptors,
00:28:10.520
and it's proposed that those could be receptors for LP little a clearance. But I think that's
00:28:17.140
speculation at the moment, and I would probably rather not comment on it too much further than
00:28:21.060
to just observe the outcome. Now, there's one other thing that I think is worth kind of talking
00:28:28.980
about here, and that is that across all of these CETP programs, there appears to be either kind of
00:28:38.220
a neutral effect or even possibly a favorable effect on incident diabetes. Now, again, we're
00:28:43.860
going to see more of that in Obocetrapid because we have more trials. And while I think it's too
00:28:48.920
soon to say if these are definitive, they are notable because as we've talked about in the past,
00:28:55.180
statins are indeed associated with a small but real increase in the risk of type 2 diabetes.
00:29:02.380
And so I just want to point out that if, in fact, this benefit is confirmed of what we would call
00:29:08.920
metabolic neutrality or even benefit, I think it tells us a couple of things. One, it says that the
00:29:15.060
negative impact that statins have on insulin resistance are not necessarily a product of
00:29:23.000
the reduction in cholesterol and rather must be some other issue associated with the statins.
00:29:28.140
We've talked about this elsewhere that it might have to do with the impact that statins have on
00:29:32.140
the gut. But more importantly, I think it says that if we have a drug that is lowering LDL-C
00:29:38.420
and ApoB and LP little A, and it's metabolically beneficial, boy, this is a drug that has a lot
00:29:47.060
of potential benefits. So all of this is to say we've got a drug that lowers LDL, ApoB,
00:29:55.100
reduces LP little A, remodels HDL particles, potentially, at best, probably no adverse
00:30:01.380
metabolic trade-offs, maybe some benefits. And all of this is looking very promising.
00:30:06.040
We are awaiting the results of the PREVAIL phase three trial, which is a cardiovascular outcome
00:30:11.640
study. So just a word on the differences in approval. In Europe, where this drug has already
00:30:16.680
been approved, or the data are at least are sufficient for approval, the drug should be on
00:30:21.020
the market in Europe in Q4 of 26. Europe is able to approve drugs based on well-understood biomarkers,
00:30:28.400
and this is clearly an example of that. In the US, we will wait until heart outcomes are done.
00:30:33.920
So until you see a mortality benefit or a MACE reduction, major adverse cardiac event reduction,
00:30:39.520
this will not be approved. So the US is going to lag by a couple of years here.
00:30:43.880
Let's talk about what I really wanted to talk about. It's not that I didn't want to talk about
00:30:46.500
all this stuff. I really did. But I want to now get into the part that is super exciting to me,
00:30:50.820
which is brain biology and ApoE. So the brain is one of the most lipid rich organs in the body.
00:30:58.140
And of course, cholesterol is one of the most important structural components of
00:31:01.920
neuronal membranes, synapses, and mylon. So without cholesterol, the brain is not going
00:31:06.900
to function. But there's a catch, right? The brain lives behind a paywall. We call it the
00:31:11.720
blood-brain barrier. It's not really a paywall, but I just wanted to say that. So the brain lives
00:31:15.900
behind a blood-brain barrier. And that blood-brain barrier separates the brain's cholesterol economy
0.97
00:31:22.620
from the rest of the body. So the lipoprotein particles that we measure in the blood are
00:31:28.800
essentially sequestered from the brain. And as such, the brain cannot rely on circulating
00:31:34.720
cholesterol the way the liver can. Instead, the brain runs its own semi-independent lipid
00:31:41.840
management system, which transports its own lipoproteins. Now in the periphery and the rest
00:31:48.500
of the body, outside of the blood-brain barrier, cholesterol balance depends on a very coordinated
00:31:52.860
system of lipoprotein particles. We've talked about this, right? So we talked about the HDL
00:31:56.520
particles, which are built around APOA1. They accept cholesterol from cells, transport back
00:32:01.640
to the liver, sometimes give them to LDLs that take them back to the liver. All of this stuff
00:32:05.620
is going on. And I didn't even get into the rest of that stuff, but we know that as the liver
00:32:09.780
excretes bile, bile travels through the gut. The gut has another check in there where it gets to
00:32:16.200
bring cholesterol in, determine if we need it or not. If not, we excrete it. If yes, we bring it
00:32:21.280
back in. The body is really, really pretty marvelous when it comes to this. But the brain
00:32:26.260
uses a very different set of proteins to mediate this. Now, instead of using APOA1, which is the
00:32:34.420
protein on the HDL that is largely responsible for this accounting, its lipoproteins, the one
00:32:39.960
the brain are organized around something called apolipoprotein E or ApoE. So astrocytes and
00:32:47.200
microglia synthesize ApoE-containing particles that shuttle cholesterol and phospholipids to
00:32:53.880
neurons. These particles support membrane repair and synaptic remodeling and basically the overall
00:32:59.800
lipid homeostasis within the CNS. Now, the efficiency of that system, of course, turns out
00:33:06.380
to be highly genotype dependent. So most people carry two copies of an isoform for the gene that
00:33:15.820
makes this protein called ApoE3. So there are three isoforms, ApoE2, ApoE3, and ApoE4. This is
00:33:23.920
a bit of the problem with the nomenclature here. Whenever I'm talking about the gene, I'm talking
00:33:27.680
about the all caps version. So capital A, capital P, capital O, capital E, and then the number,
00:33:33.000
2, 3, or 4. You get two of those, two genes, one from mom, one from dad. So there are six
00:33:41.280
possible combinations, right? 2, 2, 2, 3, 2, 4, 3, 3, 3, 4, 4, 4. Each of those will yield a slightly
00:33:49.320
different protein. The protein is called APOE, no number, just APOE, and it's no caps. So it's
00:33:55.480
just little a, P-O-E, no caps. So that's how you know if you're thinking about the protein or
00:34:00.540
thinking about the gene that codes for the protein. So if you look at the ApoE protein
00:34:06.420
that is made by two copies of the ApoE3 gene, we call this the wild type, it handles cholesterol
00:34:12.980
transport in the brain really well. But if you look at the protein, the ApoE protein, that is
00:34:18.880
made by one or two copies of the ApoE4 gene, it does not. So if you look at the protein made from
00:34:27.720
one or two copies of an APOE4 gene, it's less efficiently lipidated. It interacts differently
00:34:32.160
with transporters, and it forms lipoprotein particles that are less structurally stable
00:34:37.220
and less effective at moving cholesterol. And what's really amazing, by the way, as an aside,
00:34:42.440
is all of this comes down to a single amino acid substitution. And for anybody who cares,
00:34:47.720
it's a cysteine to an arginine substitution at position 112. And that one little change
00:34:55.540
alters the protein's shape and all of its downstream behaviors. And of course, this isn't
00:34:59.900
unique here. I mean, if you look at something like sickle cell disease, it's the same sort of thing.
00:35:03.440
It's one amino acid substitution that completely changes the way a red blood cell functions,
00:35:09.500
in this case, you know, through hemoglobin. So why do we care? Well, we care because if cholesterol
00:35:14.840
isn't properly transported, it's going to build up. And lipid droplets that form inside of
00:35:21.320
astrocytes and microglia, they cause problems, right? The membrane composition shifts, oxidative
00:35:27.080
stress, because remember cholesterol is highly sensitive to oxidative stress. That's what's
00:35:30.980
leading to atherosclerosis. It increases, amyloid clearance becomes less efficient,
00:35:36.220
and inflammatory signals rise. And if that sounds like a bad thing, then you understand enough about
00:35:40.760
Alzheimer's disease already, which is amyloid accumulates, inflammation increases, and over a
00:35:48.100
long enough period of time, often decades, this impaired ability to traffic lipids is what
00:35:54.220
contributes to synaptic dysfunction and ultimately to neuronal death. So this is why APOE4 is a
00:36:02.320
concern. If an individual has one or two copies of this gene, they are at an increased risk for
00:36:07.520
Alzheimer's disease. Now, we also know that this is not a deterministic gene. There are lots of
00:36:12.680
people that are walking around with APOE4 genes that are doing just fine in advanced age. So I
00:36:18.220
don't want to be sitting here sending fear signals to those individuals. But we have to acknowledge
00:36:22.760
that on average, statistically speaking, if you have one or two copies of that gene,
00:36:28.100
you are basically getting sped up in your brain aging. And what that effectively means is if you
00:36:35.720
have two copies of an ApoE4 gene, your probability of developing clinically significant cognitive
00:36:42.820
decline is going to be about two decades sooner than a person who's got two copies of an ApoE3
00:36:49.960
gene. Again, that's on average. It's not for everybody. There are lots of things that can
00:36:54.860
modify this. We've talked about some of them. We've talked about Clotho, KLVS. We've talked
00:36:59.240
about all the lifestyle factors that can make a difference. But I just want to acknowledge the
00:37:03.460
obvious here. Now, I think kind of at first glance, I think, you know, CTEP inhibition might
00:37:09.840
not really matter to this discussion because it operates in plasma, where it facilitates
00:37:17.840
the exchange, as we talked about, between cholesterol ester, between the different
00:37:22.680
particles of lipoproteins, right? The cholesterol esters that move between HDL and LDL. And this
00:37:28.060
creates a larger HDL particle where APOA1 stays on longer and it's cleared more slowly. So again,
00:37:35.380
APOA1 concentrations increase. That's why we see HDL cholesterol go up. So what does this have to
00:37:40.820
do with the brain? Well, APOA1 is a relatively small protein. And therefore, small lipid poor
00:37:48.960
HDL particles, which contain APOA1, can indeed cross the blood-brain barrier in limited amounts.
00:37:55.800
So by increasing the circulating pool of APOA1, the CTEP inhibitors can increase the availability
00:38:05.100
of functional APOA1 within the CNS. And so in the context of APOE4 patients, where endogenous
00:38:13.860
lipid transport is less efficient, a greater concentration of APOA1 could augment cholesterol
00:38:20.220
efflux and at least partially offset the impaired functioning APOE protein, right? The APOE-mediated
00:38:30.920
trafficking of that protein. Now, in addition to that, of course, obacetropib confers all the
00:38:38.560
usual cerebrovascular benefits through the well-established atherosclerotic actions by
00:38:45.200
lowering ApoB, etc. In addition, functional HDL particles can carry lipophilic antioxidants as
00:38:55.060
well and move them. So basically increasing HDL concentration, especially HDLs that are small but
00:39:02.160
yet functional that can still get into the CNS, may raise the antioxidant content within the
00:39:08.220
circulating HDLs and to a limited extent within the CSF. So enhanced antioxidant availability
00:39:14.420
could help attenuate the oxidative stress and lipid peroxidation process, which of course is
00:39:20.000
also known to amplify neuroinflammatory signals. Now, again, this framework is somewhat speculative,
00:39:27.440
but it is biologically coherent. It also offers a plausible explanation for why the most
00:39:36.480
pronounced biomarker effects in the Broadway sub-study, which I'm going to discuss here in a
00:39:42.000
second, are observed in the APOE4E4 individuals, because this is a group in whom lipid trafficking
00:39:50.480
is the—the dysfunction of lipid trafficking, I should say, is the most noted. And therefore,
00:39:56.300
this group, in theory, should benefit the most from everything I just said. Okay, so let me just
00:40:01.380
go back to the study, because I'm kind of getting ahead of myself in the spirit of trying to explain
00:40:04.400
the biology. So let's go back to the Broadway study. So remember, this is the one where there
00:40:09.080
was a pre-selected endpoint. So the investigators pre-selected a subset of this study to look at
00:40:18.800
the biomarkers of Alzheimer's disease. And the primary endpoint was a change in plasma
00:40:25.480
phosphorylated tau 217, known as Ptau 217, over the period of 12 months from baseline to a year
00:40:34.760
out. They also looked at some secondary endpoints, which were changes in the ratio of P-tau-217
00:40:40.660
to amyloid beta 42 to 40 ratio, and then P-tau-181, something called glial fibrillary
00:40:48.100
acidic protein, or GFAP, and neurofilament light chain, or NFL. I just want to point out that P-tau-217
00:40:57.640
is probably the most important of these, at least we believe that today, because it is the most
00:41:03.400
highly correlated with the findings that we see on a type of PET scan that is used to measure
00:41:11.880
tau. And that PET scan and its results tend to be the most highly correlated with the clinical
00:41:18.140
outcomes that we see. So that's why they chose Ptau217 as the primary endpoint. The participants
00:41:24.720
were stratified by their APOE genotypes. Specifically, they looked at 3-3s, 3-4s,
00:41:30.600
and 4-4s, and then all the related subgroups. Okay. So in the final biomarker analysis,
00:41:36.160
there were over 1,500 participants, median age of 67, two-thirds of them are male.
00:41:42.660
Now, these are patients without dementia or cognitive impairment, but they did have
00:41:48.740
cardiovascular disease. It's always important to just remember what your patient population was.
00:41:52.920
Let me spend one more second just going over the biomarkers. So as I said, plasma P-tau,
00:41:58.680
probably the strongest predictor we have in the periphery that correlates with Alzheimer's
00:42:02.400
pathology. Again, I mentioned why, right? Amyloid PET positivity and tau aggregation
00:42:08.280
are probably the best thing we can do to predate clinical stage symptoms.
00:42:14.420
AB 42-40 ratio reflects amyloid biology. So as AB 42 becomes sequestered into plaque
00:42:21.020
with the brain circulating, AB 42 declines relative to 40, which lowers that ratio.
00:42:26.800
If you look at P-tau-217 to that ratio, it just integrates these two.
00:42:32.780
GFAP is a marker of astroglial activation, and NFL is a marker of axonal injury and neurodegeneration.
00:42:40.920
It's not specific to Alzheimer's disease, by the way, but when levels are rising, it indicates neuronal damage.
00:42:47.320
So if we take these things together and look at the results, what did we see?
00:42:52.000
So across all participants, Obacetrapib significantly attenuated the increase in
00:43:01.580
P-tau-217, the primary outcome, compared to placebo over 12 months. So if you take everybody,
00:43:08.400
the adjusted mean percentage increase in the placebo group was 5%. So P-tau-217 went up by 5%
00:43:16.200
across everyone in the study over a year and in the placebo group. And then the obocetrapib group,
00:43:22.260
it only went up 2%. Now, what's interesting is if you start to look at the subgroups. So in the
00:43:29.020
subgroups, if you look at just those that had an E4, so this was people who were E3, E4, or E4,
00:43:40.040
E4, the difference is a little more stark. In the placebo group, you saw an increase of PTA217
00:43:47.440
by over 7%, whereas in the Obacetrapib group, it only went up about 1.5%.
00:43:54.040
Now, what if you just looked at E3, E4, and E4, E4 in people over the age of 70?
00:44:02.620
So again, what we're doing is we're taking that same population, but now we're looking at the
00:44:06.360
people who are at even higher risk just based on age. And here we saw that in the placebo group,
00:44:14.540
Ptau-217 over the course of a year rose by almost 15%, but it went up only by 6% in the
00:44:22.560
obocetrapib group. Again, that was statistically significant. But the most interesting finding
00:44:27.900
for me, and I think anybody who would look at the paper, is what happened in the admittedly
00:44:33.280
small subset, 29 people, of E4, E4s of any age. In this population, the placebo group saw an
00:44:43.100
increase of almost 13%, 12.7% of PTAO-217 over the course of a year. And yet in the group on
00:44:53.340
Obacetrapib, they actually saw a reduction in PTAO-217 by nearly 8%, creating a difference
00:45:00.600
of over 20% between those treatment groups. And that was, again, highly statistically significant
00:45:06.880
despite the small number. So all of this is to say that something really interesting could be
00:45:15.520
happening in these APOE4 patients. Now, again, as I want to say, it's a very small subgroup,
00:45:22.000
right? So this is a 1,500-person trial. 29 of those people were E4E4. As a general rule in
00:45:27.920
the population. E4, E4 is about 2% of the population, but E3, E4 is about 20 to 25% of
00:45:34.140
the population. So there's still a lot of people out there who would benefit from this. We're just
00:45:38.260
seeing an enormous impact in these people. In the overall population, again, the effect size is
00:45:46.060
statistically significant. We don't know if it's clinically significant. I won't go into all the
00:45:51.520
other biomarkers just for the sake of time, but we're going to link to the study in the show notes
00:45:55.560
so you can look and see all of the other biomarkers, but everything moved in the right
00:46:01.320
direction. There was not a single biomarker for which Obacetrapib didn't do exactly what you
00:46:09.840
would want it to do. This was true in PTAO 217. This was true in NFL, GFAP. Of course,
00:46:18.140
the impact was most notable and most significant in the E4E4. So there's one figure that you can
00:46:24.460
look at, where you see the effect on the E4, E4s, and it's profound. So I'll go over that figure
00:46:30.220
because I already gave you the PTAO 217, where you see a 20% difference between placebo and treatment.
00:46:36.500
In the NFL, it's a 17% difference. In the GFAP, it's a 15% difference. In the PTAO 181,
00:46:43.300
it's almost a 14% difference. In the AB 42 to 40 ratio, it's about an 8% difference.
00:46:48.880
And in the ratio of the ratio, the P-tau to the AB4240, it's almost a 23% difference.
00:47:01.560
So first and foremost, this is a biomarker study.
00:47:05.400
There were no formal cognitive tests that were included here.
00:47:08.760
And we don't know for certain if these biomarker changes would translate into preserved cognition
00:47:16.640
or a slower decline or reduced incidence of dementia. As I said, PTAL217 is a very well
00:47:22.840
validated biomarker. So everything looks very optimistic, but without the outcome trial,
00:47:28.220
we don't know. Second thing we don't know is this is a short study. It was only 12 months.
00:47:32.320
Alzheimer's is a disease that unfolds over decades. Do we know if we looked at over a long
00:47:38.660
enough period of time, would this benefit be maintained? I already talked about the size of
00:47:43.060
the subclass, very small group. Sometimes you can see extraordinarily results in small groups,
00:47:47.700
and it's a bit of a weird statistical outlier, and we don't know what it's going to look like
00:47:50.560
in a larger cohort. I think the last point I would make here is less of a knock, but it's just
00:47:56.320
we don't know exactly why this is happening. Now, to be clear, we don't know why clotho works either,
00:48:01.080
and yet we still think it's very exciting and interesting. We don't know how clotho works. I
00:48:04.900
mean, we don't even understand how clotho impacts its targets in the brain since it doesn't appear
00:48:10.220
to cross the blood-brain barrier. So all of that is to say, we know a bunch of things that
00:48:15.860
opacetrapib does. We know that it modifies HDL particles and lowers LDL and ApoB, reduces LP
00:48:20.800
little a, but it's hard to say which of these are the ones that are contributing. And I personally
00:48:26.480
find the HDL ApoA1 story to be the most compelling argument here. So what can we conclude? So I think
00:48:32.720
we can say, look, this is a biomarker study that was internally coherent and very genotype specific.
00:48:39.200
and I think it has very high biologic plausibility. I think we have to be cautious because biomarkers
00:48:46.980
don't necessarily establish clinical benefit. We need more data, but I'm very excited. And I think
00:48:53.840
personally that this signal is strong enough to justify a dedicated prospective prevention trial
00:49:00.340
that should include cognitive outcomes, imaging, longer follow-ups, and frankly, larger genomic
00:49:07.480
stratified groups. Now, such a study would need to be enriched for APOE4 carriers. So we'd want
00:49:14.340
lots of E3 and E4. So if I were designing that study, I'd want every E44 on the planet that I
00:49:22.280
could get enrolled in that study, and I'd want basically two-thirds of the patients to be at
00:49:26.260
least a 3-4. In my mind, you want people who are completely cognitively intact in mid-life or
00:49:33.560
slightly older. So these are probably people in their 60s, maybe 70s, but again, completely
00:49:40.600
cognitively intact, no evidence of MCI. And you're going to need to track these people for quite a
00:49:45.960
long period of time. So it's going to need to have longitudinal cognitive endpoints that are going
00:49:50.760
to be sensitive to early decline. It's going to have to have serial plasma biomarkers, maybe some
00:49:55.620
imaging studies, including amyloid or tau PET. And it needs to run for several years. So look,
00:50:01.160
I'm not suggesting that this is an easy thing to do. I'm just suggesting that if we lived in a
00:50:05.400
parallel universe where resources were unlimited, that's the study that you would do to figure this
00:50:10.460
out. So look, it's hard for me to mask my personal optimism around this. I love the biological
00:50:17.480
plausibility of this. And I think that Obocetrapib has done something that its four predecessors has
00:50:24.940
failed to do. And I think if it did nothing else, but have the impact that I think it's going to
00:50:30.000
have from a cardiovascular disease standpoint, which is to say it's going to have a significant
00:50:34.800
impact on LDL-C and ApoB. I believe it will likely show a reduction in events, certainly over a long
00:50:40.760
enough period of time. The impact on LP little A is very interesting to me. And the fact that it
00:50:46.020
is metabolically neutral or potentially positive is also very exciting. And then you layer this on
00:50:51.640
as well. This is a drug I'm very excited about. And I look forward to learning more about the
00:50:58.620
approval process in the United States. Again, I don't know exactly where it is in that life cycle,
00:51:03.980
but I know it'll probably still be a couple of years after the European approval, which will
00:51:08.540
lead to the launch of this drug in the second half or last quarter of 2026. So that'll wrap up
00:51:17.320
our story on Obacetrapib. Hope you guys found that as interesting as I did.
00:51:22.080
Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com
00:51:29.160
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