The Peter Attia Drive - March 16, 2026


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


Episode Stats

Length

52 minutes

Words per Minute

164.28694

Word Count

8,641

Sentence Count

468

Misogynist Sentences

1


Summary

Summaries generated with gmurro/bart-large-finetuned-filtered-spotify-podcast-summ .

Transcript

Transcript generated with Whisper (turbo).
Misogyny classifications generated with MilaNLProc/bert-base-uncased-ear-misogyny .
00:00:00.000 Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Atiyah. This podcast,
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00:01:04.300 Welcome to a special episode of The Drive. In this episode, I take a slightly different approach
00:01:09.180 where I'm going to walk you through a single topic in depth, breaking down the science behind,
00:01:14.680 in this case, a drug that caught my attention and has me very excited. The drug is called
00:01:18.960 Obacetrapib. So I'm going to explain what it is, why it's generating renewed interest in
00:01:24.460 cardiovascular medicine, at least as a class of drug, and why the emerging data may also have
00:01:29.380 implications for Alzheimer's disease, particularly for those who carry an E4 allele. So in this
00:01:35.380 episode, I'm going to discuss what Obacetrapib is, how it works as a class of drug called a CETP
00:01:41.620 inhibitor, the history of these drugs, and why the previous versions of them have failed,
00:01:46.560 and in some cases spectacularly, the key clinical trials behind Obacetrapib and why they were
00:01:52.860 designed, what they were designed to measure, the drug's effect on the major lipid biomarkers,
00:01:57.800 including LpA, all very interesting, a study called the Broadway Biomarker Study and its
00:02:02.740 findings in Alzheimer's-related blood biomarkers, again, including a very interesting subgroup in
00:02:07.840 APOE carriers. And I guess most of all what these results mean, how do they have me thinking about
00:02:13.680 this drug for my patients. So without further delay, I hope you enjoy this special episode of
00:02:18.720 The Drive. So if you spend any time thinking about Alzheimer's disease research, you get
00:02:28.740 pretty familiar with the emotional whiplash that accompanies it. You know, one week you're going
00:02:32.900 to see a biomarker that moves and people talk about it and you'll see reportings all over the
00:02:39.620 sort of lay press. And then the next week, some trial misses and the whole idea gets dismissed.
00:02:44.920 And I think that's understandable for reasons maybe beyond the scope of what I want to talk
00:02:48.920 about today. And I think it's also really true in the cases of prevention because prevention
00:02:53.680 trials are hard to conduct. They take a long time. They're very expensive. And early signals
00:03:00.760 can look compelling even before something's actually proven. So with that as background,
00:03:06.340 Today, I'd like to talk about a drug called Obacetrapib. Now, this is a drug that's primarily
00:03:12.400 being investigated because of its ability to reduce LDL cholesterol and with it ApoB.
00:03:18.280 And I'm going to talk about that as part of the story. But more broadly, I want to talk about
00:03:22.760 this drug in the spirit of cautious optimism as it pertains to Alzheimer's disease. So here's
00:03:29.260 why it's interesting. Obacetrapib is a CETP or CTEP inhibitor, which is a class of drug
00:03:34.860 with a very complicated and quite honestly, a very fascinating history in cardiovascular
00:03:39.680 disease medicine. I'm going to actually talk about this in detail because I think it's important to
00:03:43.600 the story. But in a recent large phase three lipid trial, there was a pre-specified biomarker study
00:03:51.660 that looked at Alzheimer's related blood biomarkers for a period of about 12 months.
00:03:57.160 And in these studies, or in this study rather, the investigators saw an attenuation of P-tau-217
00:04:03.760 progression with a very strong signal in the APOE44 individuals. So this combination,
00:04:12.980 which is basically a revived drug, a drug that there's lots of examples of this class of drug
00:04:18.340 in the graveyard, plus a coherent biomarker movement coupled with real genotype specificity
00:04:25.920 is in my mind what makes this a very exciting topic that I want to kind of share with you all
00:04:31.280 today. So to set expectations, I'm not going to come away from this proving that obocetripib
00:04:36.160 prevents Alzheimer's disease or delays even cognitive benefits. But I will say that I haven't
00:04:41.860 been as excited about any drug in the market or a drug that's about to enter the market as I am
00:04:46.760 with respect to this drug. So what do I want to accomplish here today? First, I want to kind of
00:04:51.320 revisit the story of CTEP inhibitors, why so many of them have failed. I want to explain why maybe
00:04:57.420 this drug is not failing, explain why lipid biology intersects with Alzheimer's disease,
00:05:02.960 especially in the E4 carriers. I want to walk through the very specific study that is leading
00:05:08.660 me to have this optimism. It's called the Broadway study. And I want to talk about what I hope happens
00:05:14.380 next so that we can figure out whether this needs to be a part of everybody's life who's at risk.
00:05:19.820 So to start, let's get into CETP or CTEP biology. Now to understand why this class of drug works,
00:05:30.700 you have to understand something called reverse cholesterol transport. And to understand how
00:05:37.260 reverse cholesterol transport works, you kind of got to go back and understand lipoproteins.
00:05:42.300 So apologies in advance for those of you that are already completely up to speed on lipoproteins,
00:05:46.780 but I just want to make sure everybody's playing on the same level. Now, the way I talk about this
00:05:51.780 with my patients is the way I'm going to kind of talk about it with you, which is to say
00:05:54.820 that there are broadly speaking two classes of lipoproteins. Let's not forget why we have
00:05:59.840 lipoproteins. Lipoproteins exist so that we can move cholesterol through our bloodstream. Why is
00:06:06.060 that important? Well, there's several factors. The first is every cell in the body needs cholesterol.
00:06:10.760 It's a vital ingredient for our existence. If we didn't make cholesterol, we wouldn't actually be
00:06:16.100 alive. And not every cell can necessarily make enough at every moment in time. So while every
00:06:23.060 cell can make it, cholesterol needs to be shared across the body. Now, the problem with cholesterol
00:06:27.400 is it is not water soluble. So the fancy word for that is it is hydrophobic. And so something that
00:06:34.120 is hydrophobic or something that repels water can't be transmitted through the blood because
00:06:39.340 the blood is water. Our blood is plasma and a bunch of proteins. So the body has to come up
00:06:45.160 with a slick way to do this. Again, the body has no trouble transporting things that are
00:06:49.400 water-soluble, right? So proteins, electrolytes, ions, these things move easily through the blood.
00:06:55.340 Glucose, for that matter, right? Just doesn't need anything to carry it. Not the same for
00:06:58.860 cholesterol. So we evolved these cool things called lipoproteins, which as the name suggests,
00:07:04.280 are part lipid, part protein. The lipid or cholesterol fits on the inside, so it's shielded
00:07:10.260 from the hydrophilic exterior, and the proteins are on the outside, which is what allows it to
00:07:16.700 transmit through the blood. Now, you can broadly divide these into two classes. There's an ApoB
00:07:22.340 class, and there's an ApoA1 class. The ApoB class is the one you've heard me talk about a ton,
00:07:30.000 because those ApoB lipoproteins are the ones that cause atherosclerosis. Now, they're mostly LDLs,
00:07:35.820 But we shouldn't forget how they start. They start out as VLDLs, very low-density lipoproteins,
00:07:42.320 which are really big. And they show up in all sorts of sizes. They cascade from a V6 to a V1
00:07:49.680 in size. They spend a tiny, tiny fraction of time as IDLs, intermediate-density lipoproteins,
00:07:55.260 before ultimately maturing as LDLs, or low-density lipoproteins. And so if you did a blood test,
00:08:00.260 you might look at the cholesterol concentration of these. You would never be able to catch an
00:08:05.040 IDL, but you would certainly catch the VLDL cholesterol, and that level might be, you know,
00:08:09.760 15 to 20, maybe as high as 30 milligrams per deciliter. And then you would look at the LDL
00:08:15.000 cholesterol, and you would see a much bigger number. Now remember, the LDLs are actually
00:08:19.020 smaller, but you have so many more of them than the VLDLs, and therefore you're going to, in
00:08:24.280 aggregate, find much more cholesterol per unit volume of plasma. Now on the other side of the
00:08:30.760 ledger, we have these things called HDLs, or high-density lipoproteins, and they're structurally
00:08:37.300 different. They come from a different lineage, and they have a different lipoprotein that wraps
00:08:43.180 around them, and that lipoprotein is called APOA1. This is going to be important as we get into our
00:08:49.280 story. So what is reverse cholesterol transport? Well, historically, it has simply been viewed as
00:08:57.320 HDLs returning cholesterol molecules from the body to the liver. And so, you know, if you asked
00:09:05.300 me 10 years ago to tell you what RCT or reverse cholesterol transport was, that's what I would
00:09:09.620 have said. I would have said it's when HDLs take, they delipidate, you know, for example,
00:09:14.840 plaques in the coronary arteries and they'll, or they take a sort of cholesterol out of other
00:09:19.380 tissues and they bring it back to the liver. But I think we would now want to more technically
00:09:24.220 refer to that term as HDL or APOA1-mediated trafficking of cholesterol. And again, that
00:09:32.100 process is when a peripheral cell exports excess free cholesterol to that protein, the APOA1
00:09:39.580 protein that forms the HDL particle. That cholesterol is then packaged into a more stable
00:09:44.060 form, carried with the HDL particle, returns back. Okay. Now, the direct RCT or reverse
00:09:49.520 cholesterol transport is when the HDL delivers that cholesterol straight into the liver, sometimes
00:09:55.180 the intestine, and it unloads it there via a receptor called the sterol receptor binding one
00:10:01.640 or SRB1. I only mentioned that because I'm going to bring it up later. I don't actually care if
00:10:05.620 you remember that, but just remember that HDLs can take cholesterol directly to the liver and
00:10:10.020 they deliver it through that receptor. But there's also something called indirect RCT.
00:10:15.720 I don't think I even learned what indirect RCT was until maybe eight or nine years ago,
00:10:20.800 which is not to say it wasn't understood before then.
00:10:23.040 I'm just telling you I didn't understand this before then.
00:10:25.300 And here is where this is actually kind of cool.
00:10:27.060 The HDL doesn't deliver the cholesterol itself.
00:10:29.320 Instead, it exchanges its cholesterol ester, which are the cholesterol molecules bound
00:10:36.720 to long-chain fatty acids.
00:10:38.100 So that's a cholesterol ester and cholesterol are cousins.
00:10:40.640 and exchanges those things for the triglycerides inside the ApoB particle, which is usually the
00:10:47.800 LDL. So let's just go back and say that again. So you got an HDL that's full of cholesterol
00:10:53.720 ester. It bumps into an LDL in the periphery, which has got a bunch of triglycerides in it.
00:10:59.600 They swap triglyceride for cholesterol ester. And then those LDL particles,
00:11:06.760 quote-unquote bad guys, do a good thing. They take cholesterol back to the liver.
00:11:12.520 Now, it's important to understand that an enormous amount of reverse cholesterol transport takes
00:11:19.000 place via this route, some 40% to 50% of it. So, you know, it's important to understand that LDLs
00:11:25.880 aren't all bad. They are doing this one good thing. Now, I know what you're thinking. If we
00:11:30.920 lower our LDLs, does that mean we get less reverse cholesterol transport? No, the direct pathway
00:11:36.440 just picks up the balance. But it's just an interesting thing to observe here. Okay, now what
00:11:40.660 does all this thing have to do with CTEP? Well, what does CTEP stand for? I said it, I think,
00:11:44.420 at the beginning. It stands for cholesterol ester transfer protein. And so at a high level,
00:11:50.080 you can think of the CTEP as a molecular shuttle that exchanges the cholesterol ester in the HDL
00:11:55.040 for the triglyceride molecule in the LDL as part of this indirect reverse cholesterol transport
00:12:00.120 pathway. Now, because CTEP mediates an exchange of cholesterol ester from HDL for triglyceride
00:12:06.840 in the ApoB-containing particles, it doesn't just move cholesterol, it actually reshapes
00:12:12.000 the particles themselves. And so when CTEP activity is high, more cholesterol esters
00:12:18.840 enter, pardon me, leave the HDL and move into the LDL. So HDL becomes cholesterol poor
00:12:27.340 and triglyceride-rich, while LDL becomes cholesterol-rich and triglyceride-poor.
00:12:34.360 Okay, but remember, while we like the idea of cholesterol going back to the liver, if you just
00:12:41.340 load those LDLs of cholesterol, we know where they're ultimately going to end up. So this is
00:12:46.240 not a condition we want. So the problem with too much CTAP activity is that the triglyceride-enriched
00:12:53.600 HDL is unstable. It gets rapidly trimmed down by enzymes called lipases, both in the liver and at
00:13:02.060 the endothelium. These produce smaller HDL particles that can either be rebuilt or cleared
00:13:08.040 from circulation. But what happens is that you have those cholesterol-enriched LDL particles that
00:13:13.240 will ultimately go back to the liver, but may not, right? They may also end up ending up in
00:13:18.920 artery walls. So that's what's happening when CTEP is activated. And so what happens if you
00:13:25.220 inhibit CTEP? The opposite happens. So less cholesterol ester leaves HDL. This results in
00:13:32.200 much larger cholesterol-rich HDL particles. So HDL cholesterol, the biomarker, goes up,
00:13:39.720 and LDL cholesterol, the biomarker, goes down. All right. So with that as background, I think
00:13:46.180 we can now talk about what I think is a very fascinating history of this class of drug called
00:13:53.180 CETP or CTEP inhibitors. Now, it's important to understand the context of this. So in the 90s,
00:13:59.900 I think around the 90s when this class of drug were first developed, the excitement was almost
00:14:05.880 entirely around the HDL story. What do I mean by that? Well, the CTEP inhibitors, these first
00:14:13.720 versions, which we'll talk about, dramatically raised HDL cholesterol, oftentimes doubling it.
00:14:19.380 Okay. Now at the time, this term that still exists today, unfortunately, was even more prevalent,
00:14:25.980 which was that HDL was good cholesterol. And so the thinking was really straightforward in its
00:14:32.420 reductionist manner, which was if low HDL is bad because it's associated with more cardiovascular
00:14:38.540 risk, then raising HDL should be good. And therefore, giving a drug that raises HDL
00:14:46.560 cholesterol is a good thing. And that was the rationale for going forward with this.
00:14:51.700 Now, I discussed this in a podcast a couple of years ago with John Kastelin, and it turned out
00:14:57.440 that that assumption was overly simplistic, although it wasn't known at the time. So since
00:15:02.500 that time, Mendelian randomizations have been done and have actually failed to support the
00:15:10.000 hypothesis that HDL cholesterol is causally linked to favorable cardiovascular disease
00:15:17.040 outcome. By the way, that's the exact opposite of what the Mendelian randomizations have showed us
00:15:20.760 about LDL cholesterol. Every Mendelian randomization that has looked at the level of
00:15:25.120 LDL cholesterol, again, genetically controlled to a large extent, has found the opposite,
00:15:31.100 that it is indeed causally related to bad outcomes. But we don't see that with HDL.
00:15:37.900 I would like to think that if people knew that 30 years ago, it might have saved some of the pain
00:15:43.940 that was coming our way. But at the same time, maybe we wouldn't have Obisetrapib today. So
00:15:47.620 I don't want to be too much of a revisionist on history. The point here is the Mendelian
00:15:53.000 randomizations would suggest to us that simply raising HDL cholesterol is not going to reduce
00:15:57.760 cardiovascular events by itself. Another point that wasn't known at the time that is known today
00:16:02.020 that's been reinforced by human genetics is that individuals who have a loss of function
00:16:07.480 variants in CTEP have markedly elevated HDL cholesterol and in some analyses at least have
00:16:14.700 lower cardiovascular disease risk. But that benefit appears to track with reductions in
00:16:20.740 their non-HDL cholesterol, not with the increase in HDL cholesterol. In contrast, loss of function
00:16:28.560 mutations in the HDL receptor SRB1. Remember I talked about how when we were dealing with
00:16:34.520 direct versus indirect reverse cholesterol transport, the direct route is what allows the
00:16:40.820 HDL to take cholesterol straight to the liver or to the gut and transport it through the SRB1.
00:16:49.140 So if you have a loss of function mutation in the gene that codes for SRB1, what's going to happen?
00:16:55.700 You're going to have a defective transporter. Your HDLs are not going to do a good job in getting
00:17:02.720 cholesterol out of them into where they need to go. The HDL cholesterol is actually going to go up,
00:17:07.580 isn't it? So those patients walk around with very high HDL cholesterol, and yet they have a higher
00:17:12.900 increase in coronary artery disease risk. Just as an aside, a very, very close friend of mine
00:17:17.320 who I've known for almost 20 years, has always had very high HDL cholesterol and low LDL
00:17:23.500 cholesterol. And we used to always marvel at his lipid panels. You know, this was literally 20
00:17:28.160 years ago. And as I got deeper, deeper, deeper into the weeds of this a few years ago, I said
00:17:33.660 to him, hey, brother, I know your HDL cholesterol is 110 or 120 milligrams per deciliter and your
00:17:39.400 LDL cholesterol is 60 or 70 milligrams per deciliter. And that almost assuredly portends
00:17:44.460 a good outcome here, do me a favor and just get a calcium score. Because I just want to be sure
00:17:49.760 you don't have one of these SRB1 mutations. And if you do, you would look exactly like you do,
00:17:56.320 but you'd be riddled with heart disease. And unfortunately, that turned out to be the case.
00:18:00.840 And so he did have a very aggressive finding on his calcium scan and had a lot of calcium there.
00:18:07.440 Fortunately, none of it was so far along that he's not going to be totally fine. And he's now
00:18:12.520 being treated and everything's going to be fine. But I point that out to just say, do not assume
00:18:16.640 that because a person has high HDL cholesterol or low LDL cholesterol that they're necessarily safe.
00:18:21.820 Okay. So all of this is to say that the biology here is super, super complicated. Okay. So let's
00:18:28.900 now talk about the various CTEP inhibitors. So the very first of these, which again, we talked
00:18:33.100 about this on the podcast with John a few years ago, was torcetripib. And this is the one I talked
00:18:38.680 about because I really remember this one well. This was a Pfizer drug. It was put into a study
00:18:43.480 paired with atorvastatin, which was about to come off patent. And everybody was excited because
00:18:49.220 atorvastatin had all of its benefits that were demonstrated over and over again in lowering
00:18:53.840 LDL cholesterol and lowering cardiovascular events. They then pair it with this drug,
00:18:58.760 which doesn't just further lower LDL, but raises HDL. Everybody thinks this is going to be a home
00:19:03.720 run, drug gets stopped prematurely in 2006 because of increased mortality, which was secondary to it
00:19:11.520 raising blood pressure. Now, this turned out to be an off-target toxicity, meaning the drug was
00:19:17.060 doing something that was raising blood pressure that had nothing to do with CTEP. And it's
00:19:20.940 unfortunate for that drug and that company, but none of the CTEP inhibitors that have followed
00:19:25.220 have suffered that limitation. So fast forward about six years to dalsetripib, which is a Roche
00:19:30.760 drug. This raised HDL cholesterol by 30 to 40%, but it didn't really meaningfully lower LDL or
00:19:38.920 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,
00:19:56.160 but there were no good outcomes, no bad outcomes, no safety side effects, but the drug was pulled
00:20:02.620 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%,
00:20:16.920 so more than doubling HDL cholesterol. LDL cholesterol was falling by about 30%,
00:20:22.360 percent, ApoB falling by about 15 percent, and even LP little a, which I'm going to talk about
00:20:27.020 in a minute, declined by about 20 percent. But ultimately, that trial was terminated after a
00:20:33.000 median follow-up of just about two years. And in retrospect, when you looked at all of the data,
00:20:39.320 it seems that the initial belief of the LDL reduction was probably overstated. Whereas when
00:20:46.100 you looked at the relevant metric of ApoB reduction, it was about 12 milligrams per
00:20:51.480 deciliter, probably not big enough to move the needle over two years. Now, a 12 milligram per
00:20:57.420 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
00:21:15.520 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
00:21:34.500 in coronary events of 9% or 10% over a median follow-up of about four years. And there was an
00:21:41.860 extended follow-up of another two years that demonstrated a further reduction of events to
00:21:48.340 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
00:22:05.940 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
00:22:16.580 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.
00:22:27.980 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,
00:23:04.240 myself included, resent that and wish that they had just put a black box warning on it. And so
00:23:08.820 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
00:23:32.040 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
00:24:40.540 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
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.
00:46:57.100 So how do we interpret this?
00:46:59.680 Well, let's be cautious here, okay?
00:47:01.560 So first and foremost, this is a biomarker study.
00:47:03.680 It's not a cognitive outcomes trial.
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 forward slash show notes if you want to dig deeper into this episode. You can also find me
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