The Peter Attia Drive - #255 ‒ Latest therapeutics in CVD, APOE's role in Alzheimer's disease and CVD, familial hypercholesterolemia, and more ｜ John Kastelein, M.D., Ph.D.

00:00:00.000 Hey everyone, welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:15.500 my website and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:19.840 into something accessible for everyone. Our goal is to provide the best content in health and

00:00:24.780 wellness full stop. And we've assembled a great team of analysts to make this happen.

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00:00:37.340 the end of this episode, I'll explain what those benefits are. Or if you want to learn more now,

00:00:41.760 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.800 here's today's episode. My guest this week is John Castelline. John is a genetic researcher

00:00:54.320 and clinician scientist known for his work in the field of familial hypercholesterolemia,

00:00:58.920 and the development of lipid modulating drugs. He is currently a professor of genetic medicine

00:01:04.600 at the University of Amsterdam, where he leads the Department of Vascular Medicine. John has been

00:01:09.960 the main driving force behind the development of a treatment for homozygous familial hypercholesterolemia,

00:01:16.580 a severe form of FH. Now, some of you may be listening to this saying, what the heck are you

00:01:21.140 talking about? Well, it's important to understand that FH or familial hypercholesterolemia is the second

00:01:27.440 most common form of hereditary heart disease, right after elevated LP little a. And you know

00:01:34.800 from probably listening to previous versions of this podcast that elevated LP little a is

00:01:39.840 staggeringly prevalent in the population. And by extension, therefore, so too is various forms of

00:01:46.320 FH. And while we use FH as an important place to start this discussion, because it becomes an

00:01:51.620 important way to understand therapeutic options, the subject matter that we cover here is, of course,

00:01:56.840 applicable to anybody who's interested in minimizing their risk of cardiovascular disease.

00:02:02.340 John has also led several clinical trials, including the pivotal Odyssey Long-Term and Odyssey Outcomes

00:02:07.640 Studies, which helped to establish the safety and efficacy of PCSK9 inhibitors in the treatment of FH

00:02:13.360 and other forms of hypercholesterolemia. As I said, we start the discussion by focusing on familial

00:02:19.380 hypercholesterolemia. We talk about what it is, how you define it, how you can be aware if you have this,

00:02:24.300 what the genetics are that underpin it, what we do with kids that have this, etc. We then talk about the

00:02:29.140 history of CTEP inhibitors, which is indeed a sordid history. These have been a class of completely

00:02:35.060 unsuccessful drugs that have resulted in much hype and fanfare without any tangible results. However, John makes a

00:02:43.240 pretty compelling case for the most recent version of these drugs to be not only a potential game

00:02:48.440 changer, a word that I hate, for cardiovascular disease, but perhaps even more interestingly for

00:02:54.220 Alzheimer's disease and type 2 diabetes. This dovetails very nicely into our final topic of discussion,

00:03:00.520 which is that and the role of ApoE. Now, traditionally, when you hear me talk about ApoE,

00:03:05.500 I'm talking about the gene ApoE and its three isoforms, ApoE2, ApoE3, ApoE4. It's important

00:03:13.200 to understand that, of course, those genes code for a protein that goes by the same name, ApoE,

00:03:19.080 although it is not fully capitalized, and that's how when you're reading it, you know the difference.

00:03:23.220 What we talk about in this episode is what that actual protein does, and why is it that someone

00:03:28.520 with the ApoE4 gene codes for a version of that protein, which, by the way, only differs in one amino

00:03:35.680 acid from the one coded for by ApoE3, and we talk about why the protein that is coded by the ApoE4

00:03:43.720 isoform produces a much greater increase in the risk of Alzheimer's disease and cardiovascular disease.

00:03:49.940 What's most interesting to me about all of this is that it ties back very nicely to the discussion

00:03:55.620 of how this most recent CTEP inhibitor might work. And what I'm left with is a sense of profound

00:04:02.120 optimism that sometime in the next five years, we may indeed have therapeutic molecules that

00:04:08.380 we can use specifically for high-risk patients, such as those with ApoE4. So overall, I would say

00:04:14.920 this discussion surprised and delighted me much more than I expected, and I know that even though

00:04:20.720 it's a technical topic, it is something that is going to be of great interest to anybody who cares

00:04:25.760 about heart health and brain health. So without further delay, please enjoy my conversation

00:04:29.560 with Jon Castellan. Jon, thank you so much for staying up late into your evening in Amsterdam

00:04:41.440 to make time to speak with me. This is a podcast that really came across my radar courtesy of one

00:04:49.380 of my mentors, Tom Dayspring, who basically got me interested in the work you were doing and said,

00:04:55.560 look, if you'd like to speak with Jon, we might be able to twist his arm to make time for this.

00:04:59.440 And so I'm both gracious that Tom got me into your work and that he was able to convince you to

00:05:04.980 sit down with us. So am I. As you know, because you mentioned to me earlier that you've listened

00:05:11.420 to the podcast, you're probably familiar with how much we talk about cardiovascular disease.

00:05:15.860 It's not really an accident, right? I mean, it is the leading cause of death globally. I don't think

00:05:20.480 you can state the stats enough, right? I mean, the last time I looked, 19 million people died in the

00:05:26.000 world due to ASCVD. And the second place killer was cancer at something like 12 to 13 million.

00:05:34.540 So it's not even close that what we're talking about is the leading cause of death. And it's for 0.57

00:05:41.000 that reason, I think that we need to make sure that we take every opportunity to educate people

00:05:45.120 about this. And I want to start with a genetic condition called familial hypercholesterolemia,

00:05:51.520 which is probably far more prevalent than people realize. In other words, there are thousands of

00:05:58.040 people listening to this podcast who are affected by that. So tell us what FH, as it is abbreviated,

00:06:05.980 is. Yeah. So we were the first in Holland who actually had a very large scale organization to

00:06:16.240 find these people. So I trained in Vancouver. I was a visiting professor also in Vancouver by Michael

00:06:23.760 Hayden. I had my Canadian exam. So I did lipid clinic in Vancouver in a time when there were no

00:06:30.720 lipid clinics in Europe or hardly. So when I got back in Europe and I started the lipid clinic in

00:06:36.300 Amsterdam, about 60% of all my referrals were FH. And I thought, why would that be? And then when you go

00:06:44.740 back into the history of my country, my country is about the size of Rhode Island, and it has 18

00:06:49.500 million people. These people have not really moved in the past. So there are large provinces with

00:06:55.280 consanguinity. It's not consanguinity as, for example, with the French Canadians or the South

00:07:00.880 Africans, but it's nevertheless consanguinity. So we got a huge 30 million euro grant from the Dutch

00:07:08.680 government to actually start actively find these people. Because when I started doing this in our

00:07:15.620 large lipid clinic in Amsterdam, we still had mortality or severe anterior MIs at ages between

00:07:22.200 20 and 30 in men, for example. Wow.

00:07:24.960 So I can almost remember all of them. People that were fit like you, but didn't know they had an LDL of

00:07:31.480 300 mix per deciliter from their birth onwards. And actually we're playing some tennis and then 0.95

00:07:37.140 they got a massive anterior MI. And in those days, there was not much stenting yet. And so the only

00:07:42.460 thing you could do is put someone in a cardiac care unit and actually do all kind of vague superficial

00:07:47.700 things. So FH is a true autosomal dominant disease, meaning it's not sex linked. You don't need two

00:07:57.400 parents to get it. You only need one parent to get it. It's almost 100% penetrant, meaning that if you

00:08:04.840 have a robust mutation in one of the genes that cause FH, you're almost certain to get the phenotype.

00:08:13.540 And the phenotype starts very early. We have in Amsterdam, the largest pediatric lipid clinic in the

00:08:20.560 world. We have seen over 2000 children with heterozygous FH. So we know that this disease starts

00:08:27.300 very early in life, then becomes symptomatic in your teenage years in the sense that the

00:08:35.040 cholesterol that is elevated in the circulation starts depositing on your tendons, especially the

00:08:41.420 extender tendons on the dorsum of your hand and in your Achilles tendon. And then also you start

00:08:48.140 very slowly seeing the arcus. So the arcus in the eye and sometimes the deposits on your eyelids,

00:08:55.600 the xanthalasmata. And so those are the physical manifestations of the disease. And then very often,

00:09:02.340 especially in the old days, the first really serious manifestation is either angina or a heart

00:09:08.500 attack. And one of the things that is so dangerous about this disorder is that it's the plaque that you

00:09:15.000 get in FH is a soft plaque. It's a cholesterol-rich, large plaque that is very often proximal in the

00:09:23.260 coronary arteries. Meaning that if a plaque like that bursts, you either have an occlusion of your

00:09:29.480 entire LAD or you have a main stem occlusion, which kills you right on the spot. You know,

00:09:36.980 sudden death, actually.

00:09:38.840 Those sort of proximal left main or distal left main are what's referred to as the widow maker.

00:09:43.500 I want to just back up and make sure some of the stuff that you said makes sense to people. So

00:09:47.840 you said so much there that has my eyes wide open and I understand this stuff. So I just want to make

00:09:54.240 sure everybody gets it. So a couple of things. Let's differentiate when you use the word phenotype

00:09:59.540 and genotype. Let's explain to people how one defines the phenotype of FH. In other words,

00:10:06.680 what is the objective metric by which we define this condition?

00:10:12.340 So the objective metric, as with all patients, is history first. And very often in these families,

00:10:20.020 there is a family history of premature coronary disease. That's one of the first things that

00:10:25.540 speaks for these families. Then second, these people have elevated LDL cholesterol without any

00:10:33.000 other abnormality. So HDL is normal, triglycerides is normal, LDL is elevated. And you need to find

00:10:40.480 elevated LDL in first degree relatives also. So in children of that individual or in one parent

00:10:47.040 and in siblings. And with that LDL, you can reasonably construct a family tree where you

00:10:54.860 know who's affected and who's not. But unfortunately, as you undoubtedly know, there's overlap between

00:11:01.840 affected family members and affected family members in LDL cholesterol. That's why we decided a long time

00:11:09.940 ago to go for the mutation. So to go for the genotype. Because of course, for the genotype,

00:11:16.500 there is no overlap. Either you carry the mutation or you don't carry the mutation.

00:11:21.660 Now, this is where we have a bit of an issue, right, John? Because unlike, for example, LP little a,

00:11:27.720 which we've had several podcasts on, where the phenotype is unambiguous, you have an elevated level

00:11:33.940 of LP little a, the lipoprotein. The genotype is also very clear. It's a one-to-one mapping,

00:11:39.080 right? LPA is the gene that codes for apolipoprotein little a, and away we go. Here,

00:11:44.420 we have a very heterogeneous genetic set of causes. In fact, I could be wrong on this,

00:11:53.040 so please correct me. I believe I've read that there may be over 3,500 different mutations

00:11:59.380 that would roll up into FH, i.e. that would produce this phenotype of... And are we using,

00:12:05.960 by the way, an LDL-C cutoff of 190 milligrams per deciliter?

00:12:10.760 Yes, that's what we are mostly using, 190. Of course, if you start a lipid clinic and you get

00:12:17.160 referrals, there's referral bias. So the initial patients that I saw all had LDLs of 300 or more.

00:12:22.600 Now, the genotype is very interesting. So what we've done is, of course, if you start determining

00:12:30.500 a genotype, you have to be absolutely sure that your diagnosis is correct, because if your diagnosis

00:12:35.660 is not correct and you don't find a mutation, it's meaningless. So what we've done is we've used the

00:12:40.980 children as our kind of diagnostic linchpin, because if a child has high cholesterol, with the

00:12:48.920 exception of primary hypothyroidism, there's almost no other cause for elevated LDL cholesterol in a

00:12:56.880 child than FH. Right. And it's important to explain, I think, to people that, although you've alluded to

00:13:03.460 it, I want to make sure people understand. There are a lot of people walking around with an LDL

00:13:07.140 cholesterol of 200 milligrams per deciliter. Oh, yeah. But they might have triglycerides of 300

00:13:12.780 milligrams per deciliter. They might have type 2 diabetes. They might have thyroid disease that is

00:13:18.100 untreated. They might have renal disease that is untreated. There are lots of other diseases

00:13:23.960 for which a side effect is elevated LDL cholesterol. And what you're saying is, look, we've got to rule

00:13:31.140 those out, right? Yes. And therefore, we started in the children, Peter. That's my point. Yes. Because

00:13:36.940 in the kids, there's far less likely to see those other diseases. Yeah. It's almost in all the thousands

00:13:42.860 of kids we've seen where just a handful had a secondary cause for elevated LDL. The vast majority

00:13:49.880 actually all had a genetic cause. And we've published this in JAMA and in Lancet. So when we

00:13:56.520 had a cohort of 220 children where we had three-generation family of elevated LDL. So there was no doubt

00:14:05.020 that they had FH. Then we started sequencing. We could find a mutation. I mean, next generation

00:14:12.380 sequencing, everything, exon-intrum, the whole, in 95% of cases. So that is a very different number

00:14:20.840 than what you normally read in the literature for adults, where people can find 50, 60% at the max,

00:14:30.240 and they have no explanation for the other 40%. Telling you that the diagnosis, the clinical

00:14:37.100 diagnosis is not that good yet in adults, unfortunately. But it's very good in children.

00:14:44.300 95% mutation. So out of those 220 kids, 5%, which is 11 kids, we also have never, ever found a mutation.

00:14:54.320 And we've really tried. So that tells me that there are more genes.

00:14:59.620 There are mutations we don't know about yet.

00:15:01.520 Exactly. Now the 95%, if you make that 100%, then it's 95% TLDL receptor, 4.5% EPO-B,

00:15:12.760 and 0.5% PCSK9 gain-of-function mutations. So that in a country like ours is the division

00:15:21.760 between the different genes. LDL receptor, vast majority.

00:15:25.500 And here it's not that profound, right? I mean, here in the US, I was always in the impression

00:15:29.900 it's probably, call it 70, 80% is LDL receptor. It's probably more like that in the US. Yes.

00:15:38.200 And let's explain to people what's going on here. Again, I think it's worth understanding

00:15:41.360 the pathophysiology because we'll get into treatment. But when we say mutation in LDL

00:15:46.260 receptor or mutation in APO-B or gain-of-function in PCSK9 protein, explain briefly what each of

00:15:54.980 those means and why would each of those translate to the higher biomarker that people are used

00:16:00.960 to seeing, right? Everybody listening to this knows what their LDL cholesterol is, but why

00:16:04.820 would these mutations lead to 3x normal levels of LDL cholesterol?

00:16:10.040 That's actually a wonderful and very easy to understand story. So every LDL particle has

00:16:17.860 an APO-B protein kind of cringled around it, almost like a snake. And one area of that protein

00:16:25.080 is sticking out of the LDL sphere. And that is a binding domain. That is around amino acid

00:16:32.800 3,500. We actually know that. Then there is a receptor for that particle sticking out from

00:16:39.700 your liver cell, your hepatocyte. And these two bind normally. So the LDL receptor grabs the LDL

00:16:48.120 particle, and then the whole complex is internalized into the lysosome endosome where it's basically

00:16:55.240 dealt with. Now, next to the LDL receptor on the hepatocyte surface sits another protein called

00:17:03.500 PCSK9. And that protein degrades the LDL receptor. And that is the balance in nature. Because you can't

00:17:12.660 have an, at least not in the old days in evolution, you can't have an overactive LDL receptor because

00:17:18.880 then you clear every LDL particle from your circulation. So you have to have a balance. And the PCSK9 protein

00:17:24.660 that degrades the LDL receptor gives that balance. But if there is a mutant in the binding domain of

00:17:32.380 APOB, you have something that we call FH or familial defective APOB, which is basically the same.

00:17:39.780 If you have a mutation in the LDL receptor, you can't bind the APOB. And then if you have a very

00:17:46.380 active PCSK9 and you basically degrade all your LDL receptors, the end result is the same. There's not

00:17:52.660 enough LDL receptors for the LDL particles. So all three things converge at the surface of your liver

00:18:00.140 cell. And a problem with either one of the three always leads to elevated LDL cholesterol. And that

00:18:07.400 leads to all the downstream things that we just discussed. So for folks who like to anthropomorphize

00:18:12.340 things, you can picture the LDL with the APOB wrapped around it as a baseball. The LDL receptor is a

00:18:19.120 baseball mitt sticking out from the liver. And the PCSK9 protein is something that smacks the mitt and

00:18:27.760 closes it. And so basically one form of mutation is mutations that change the shape of the baseball

00:18:34.520 mitt. So it can't catch the ball or it catches it very poorly. Another mutation changes the shape of

00:18:41.240 the ball. So the ball doesn't fit in an otherwise perfect baseball mitt. And then the final mutation

00:18:46.980 is one that makes too many of the things that swat the baseball mitts. 1.00

00:18:52.380 Absolutely. But if you make the diagnosis right in a child with elevated LDL cholesterol,

00:18:57.420 you've excluded the rest. You know, his father has a high cholesterol. His grandpa had a high

00:19:02.400 cholesterol. One sibling has a high cholesterol, you know, yeah, well, this is FH. Then you do a

00:19:07.920 mutation screen. You find in 95% of cases, you can find a mutation. The vast majority is the LDL

00:19:14.200 receptor. Then comes APOB and then comes PCSK9. So in our country, PCSK9 mutations gain of function

00:19:21.380 are very rare, 0.5%. You know, another mutation that we've seen even in our practice, and we have

00:19:28.760 a very small practice, but I suspect we also disproportionately collect people who are higher

00:19:34.500 risk. But I've seen two cases of what appears to be ATP binding cassette G5, G8 loss of function.

00:19:43.580 So we see people who have FH, and I mean, I can't rule out LDL receptor defects or gain of function

00:19:51.820 PCSK9 because we're not going to do that genetic test. But what we can see is that they have levels

00:19:57.500 of cytosterol and compesterol that are more than a log fold higher than the 95th percentile. And from

00:20:07.980 that, I don't know, would you agree that we're imputing, it does change our management because

00:20:13.180 ezetimibe becomes first line, but more importantly, just as a very curious finding, would you agree with

00:20:19.440 our likely inference that that's probably the driving mutation in those people?

00:20:24.040 I would completely agree. And I'll take one little step back. So mutations in these three

00:20:30.040 genes that we just described are very prevalent in the general population. In fact, we have calculated

00:20:35.680 that they are probably like one in 250, which makes FH by far the most frequent autosomal dominant

00:20:43.920 disorder in men. Now, the Koreans and a number of other people have actually looked in children with

00:20:51.360 high cholesterol at cytosterol and compesterol levels. As you know, they should be like 12 for

00:20:58.000 cytosterol and 14 for compesterol. However, if you put the level at like 35, they find a preponderance

00:21:07.680 of kids who have increased plant sterols in their circulation, and they find mutations in ABCG5G8.

00:21:15.160 So in the old days, we thought that cytosterolimia, which is the disorder associated with ABCG5G8 was like

00:21:24.200 one in a million. That is probably a huge underestimation. And based on a number of studies in different

00:21:31.800 countries, we now think it might actually be like one in 150,000 or so, 10 times more frequent than we

00:21:38.180 originally thought. And what we also didn't appreciate is that if you are heterozygous for a

00:21:45.260 loss of function mutation in ABG5G8, you also have exactly as you said, increased cytosterol and

00:21:53.140 compesterol levels. And so very likely these disorders, especially in an advanced clinic like

00:22:00.040 yours, will coincide quite frequently because they are not rare. They are actually both not that rare.

00:22:06.680 So I have exactly the same experience. Let's go back a little bit to this clinical

00:22:12.120 presentation. We talked about it, but I think some of these physical signs might be surprising to

00:22:17.840 people that go beyond the obvious, which is atherosclerosis. So you mentioned tendon xanthomas,

00:22:24.920 you mentioned cholesterol deposits elsewhere in the body. Explain a little bit more about if we

00:22:29.900 understand why does cholesterol tend to accumulate in those particular areas, for example, extensor tendons

00:22:36.340 over flexor tendons. Do we have a sense of why that's the case?

00:22:39.780 The theory is that it's linked to movement, Peter. So that tendons that are used very, very frequently,

00:22:48.500 that there is around those tendons, there is a preponderance of macrophages and monocytes.

00:22:55.040 These monocytes, macrophages are capable of storing LDL cholesterol. And when there are enough of them,

00:23:02.340 you actually see it, you physically see it and you can feel it also. So the two most frequent places

00:23:09.840 where you'll find these deposits are the extensor tendon of your hands, which you use the whole day.

00:23:15.140 And of course, your Achilles tendon. But in my career, which as you can see on my gray hair has

00:23:21.780 has been a while, I've seen xanthomas also in the patella. And so that tendon actually on the tibia,

00:23:30.280 I've seen them under wedding rings. So actually a xanthoma under a wedding ring. I've seen them

00:23:37.880 everywhere. And then the deposits on the eyes are probably also linked to movement because you're

00:23:42.100 blinking your eye the entire day. And then you have a deposit of cholesterol in your cornea,

00:23:48.900 which is called an arcus cornealis. So it's not in your lens, it's in your cornea.

00:23:56.180 Why that is, there is a lot of conjecture about it, but I don't think people really know.

00:24:02.360 But sometimes, actually, I have made the diagnosis of FH1s in a KLM airplane. So I was kind of lying.

00:24:10.020 There was a stewardess who wanted to give me a drink and she had very blue eyes, you know, 0.95

00:24:15.540 these Dutch blue eyes. And I looked in her eye and I saw a ring. I said, when you go back,

00:24:21.020 you need to have your cholesterol checked. And she proved to have FH. So sometimes you can make

00:24:27.800 the diagnosis by really paying attention in the subway or et cetera, because also the extended

00:24:34.180 tendons on your hands are sometimes really visible. There are a number of old Dutch paintings

00:24:40.420 from the 17th century where you can still see the tendons and tomas on the hands.

00:24:46.380 Wow. And of course, they obviously had no idea what was causing that shape, but they wanted to

00:24:51.800 be as accurate as possible and they painted it. So we've established how the diagnosis is made.

00:24:56.940 Do you require the clinical manifestations for the diagnosis? In other words, if you have

00:25:06.660 a 50-year-old person who has had elevated LDL-C for as long as they've had blood tests,

00:25:14.740 so they would say to you, yep, you know, doctor, going back into my teens or 20s, I had LDL-C north

00:25:21.960 of 200 milligrams per deciliter. My doctors always said, that's too high and I didn't care,

00:25:26.500 blah, blah, blah. But now that he's standing in front of you and you examine him and he has

00:25:31.000 no evidence of xanthomas. No arcus?

00:25:34.340 Nothing at all. No physical sign whatsoever. You send him for a CT angiogram and his coronary

00:25:39.360 arteries are clean. But lo and behold, his father also has elevated cholesterol. Let's say he died of

00:25:46.600 heart disease at the age of 78. So he died, but not prematurely. Absent a genetic test, which I assume

00:25:53.660 would seal the deal. Do you say at least phenotypically he still meets criteria for FH?

00:25:59.560 And also let's assume that you've ruled out every other medical thing. So he doesn't have

00:26:02.660 hypothyroidism or kidney disease or insulin resistance.

00:26:06.340 You don't need the physical stigmata to make the diagnosis because we've seen that time and time

00:26:12.200 again. There are people for some reason that have very elevated LDL cholesterol. It is genetic.

00:26:18.260 It is dominant. It is, but it doesn't lead to the physical stigmata. What I haven't seen that many

00:26:24.920 times is what you're describing is that the CT angio is normal in a 50-year-old. So if someone

00:26:30.140 tells me that they had in their teens or late teens or when they went into the military, you know, when

00:26:35.800 they're 18, they had an elevated LDL cholesterol. And when you then see them when they're 50 and they

00:26:41.620 haven't been treated to have a normal calcium scoring and or a normal CT angio, that is really

00:26:50.200 rare for LDLs. Let's say, you know, between two and 300, that's really rare, but we've seen them.

00:26:56.380 And it's interesting is that, so there is a cholesterol overlap. It's like a Gaussian distribution

00:27:01.980 for people like you and me. Then there's also a Gaussian distribution for heterozygous FH.

00:27:07.560 There is an overlap between the two, but now we know, and Evan Stein and I have actually

00:27:12.820 published about that, is that there's also an overlap between homozygous FH and the end

00:27:19.200 of the distribution of heterozygous FH. So you can never use LDL alone as a 100% certain marker

00:27:28.120 for your normal, you have heterozygous FH or you have homozygous FH. This is a syndrome diagnosis.

00:27:35.040 So you need family members, history, and ARCUS, and this and that. And then what's also very

00:27:42.000 important is what you said in the beginning, that this is a unique LDL disease. The moment

00:27:47.280 there's elevated triglycerides, for example, and low HDL, then you immediately have to think

00:27:52.360 about something entirely different, especially in an individual that's not obese or diabetic.

00:27:57.020 Let's go back and make sure we explain to people the difference between what I assume is much more

00:28:04.420 common, which is heterogeneous FH and homogeneous FH. Can you explain to folks what that is?

00:28:11.020 The terminology I find sometimes difficult. So we know, and I'm sure you've discussed that also,

00:28:17.760 I think with Dan Rader, is that there is called polygenic hypercholesterolemia.

00:28:22.840 Now, that sometimes is so severe, the polygenic hypercholesterolemia, that it looks a lot like

00:28:29.900 heterozygous FH. And some people even say, if you've had those genes also from birth onwards,

00:28:35.600 and you've had a high LDL cholesterol, you know, from a young age, the risk of that severe

00:28:40.780 polygenic hypercholesterolemia is just the same as for heterozygous FH. I still find that difficult,

00:28:47.120 because I see when you go look at premature MI, for example, patients with premature MI,

00:28:52.760 there's a huge enrichment for real heterozygous FH. So the homogeneous heterozygous FH.

00:29:01.520 The heterogeneous FH or polygenic hypercholesterolemia, whatever you want to call it,

00:29:07.520 is in my view, still a less severe clinical picture. I've never seen people with that

00:29:14.680 side of the spectrum get heart attacks in their 20s or 30s. So we have found 25,000 heterozygous

00:29:22.020 FH patients. We've published on this. So it's a humongous database. And the monogenic,

00:29:29.920 especially LDL receptor gene mutations, and especially if they're severe,

00:29:34.920 so a premature stop codon, so you don't have any protein at all,

00:29:38.320 that is the most severe form of inherited hypercholesterolemia in my dictionary and in

00:29:45.660 my experience. But truth is, is that your polygenic or heterogeneous FH is probably much

00:29:54.080 more common, even more common than heterozygous, the monogenic form of heterozygous FH.

00:30:00.080 I want to come back to this distinction when we start to talk about therapy in as much as it

00:30:06.580 changes either the initial steps we take or the expected number of steps we take therapeutically.

00:30:13.880 But before we do, I want to put a bow on a few other things. Can you formally state again the Dutch

00:30:20.300 lipid clinic criteria? And then let me know if that sort of differs from others, because I want to make

00:30:25.900 sure that, because there are different criteria for this, correct? And I think one could argue,

00:30:31.360 maybe you're biased, but I might share your bias, that the Dutch criteria might be the most rigorous.

00:30:35.520 Is that?

00:30:36.280 There is the Simon Broome criteria. There is the WHO criteria and the Dutch lipid clinic. Now,

00:30:41.820 the Dutch lipid clinic criteria were put together by one of my coworkers, Peter Landsberg.

00:30:47.800 And this set of criteria was externally and internally validated with mutations and huge numbers.

00:30:55.900 And every time you do a comparison between the Dutch and the rest, the Dutch are winning in terms of 1.00

00:31:02.780 their power to predict FH.

00:31:05.680 So it's not unlike Max Verstappen winning the most races, also being Dutch, right? Just to clarify that.

00:31:12.960 Well, I don't know. I don't know how much of a fan you are.

00:31:15.560 I think Max Verstappen is actually totally brilliant guy and a fantastic athlete.

00:31:19.780 This is just something that you get points. So if you have a first degree relative with known

00:31:26.520 premature coronary disease, you have a score of one. Or if you have a first degree relative with

00:31:32.020 high LDL, you get one. Then if you have children or you have this xantometer, you get two. I know this

00:31:39.540 is an audio, but it's a long list. And what's interesting is that if you have a mutation,

00:31:45.960 you actually get eight. And a diagnosis of definite FH is above eight. So you have definite FH,

00:31:54.680 probable FH, possible FH, and unlikely FH, which is great because you can divide your patient population

00:32:01.960 into these categories. And as you're saying, it has a therapeutic consequence. Because if someone

00:32:07.500 has definite FH, we treat from the age of six. That's in our national guidelines. And then we start

00:32:15.460 treating immediately, just to give you a feel for that. Let's just make sure people understand what

00:32:21.820 was just said there, right? If we can, through this very rigorous diagnostic criteria that just for

00:32:28.860 the record was not developed by Max Verstappen, if we can establish that a person has FH with such a

00:32:36.660 high degree of certainty that we would call it definite, we would be treating an individual as

00:32:42.320 young as six years of age. Which means our certainty with which this person's life is at risk in as early

00:32:51.680 as the third decade of their life, i.e. in their 20s, we're so sure of that, that we would do something

00:32:58.660 that honestly, I think a lot of people who don't, especially if you don't really understand the

00:33:02.760 pathophysiology of lipid metabolism, would think that's absolutely insane. Now, I obviously share

00:33:08.780 your view, which is that's absolutely not insane. That's the only way that person's going to go on

00:33:12.180 to live a long life. But I would imagine that that's a very difficult discussion to have with

00:33:17.120 parents. Well, sometimes. Yeah, yeah. I was just about to say, it would depend on what they've

00:33:22.420 already experienced. Absolutely. It's all basically determined by family history. I have seen in the

00:33:30.300 pediatric lipid clinic, especially in the first five to 10 years, mothers with no father anymore.

00:33:37.980 So mothers in their 30s, their husband was deceased. She came with three children. And then one child had a

00:33:46.900 total cholesterol of 10, which is like 400 or something. The middle child had normal cholesterol

00:33:53.760 and the youngest child had a cholesterol of 300 or something. And so that mother really wants her child

00:34:01.340 treated. Yeah. She knows that two of her three children inherited the genes that killed her husband 0.96

00:34:09.060 at 30. Exactly. Totally unannounced. The first heart attack was the last. Terrible.

00:34:14.920 One more question, actually, John, before we get to treatment. What is your best guess

00:34:21.640 as to two things? One, the fraction of people with FH who do not go on to develop premature ASCVD. So

00:34:34.160 we'll call this the fraction of people with FH that seem immune to the phenotype. And then, of course,

00:34:40.200 the more interesting question is, what would be some plausible explanations you would offer for

00:34:46.940 that? So let's start with the easier question if it's knowable. We estimate, based on our long-term

00:34:54.140 follow-up of that large Dutch cohort, that about 5% of people escape any disease symptoms at all.

00:35:03.380 So that includes coronary artery, calcium scoring, CT angios, zentalasmata, zentomas,

00:35:11.560 arcus, anything. They seem completely immune to the elevated LDL cholesterol. Now, I have to say

00:35:19.160 that the vast majority of those are women. So that's the first thing. In men, it is extremely rare

00:35:26.860 to have that. So the majority are women. And very often, we discover those women when we go into the

00:35:34.060 family. A child is referred, total cholesterol, 380. There's no thyroid problem, no renal problem.

00:35:43.100 Then we go to the father and the mother and the uncles. And then we find an aunt who's 76, has never

00:35:50.340 been treated. And we measure cholesterol. And she also has an LDL of 250. And then we do mutations because

00:35:56.740 in Holland, the mutation screening is free. The government pays for that. So we do mutations

00:36:02.180 in every one that comes to our clinic, basically free. And so then we find a mutation in her too. 0.96

00:36:08.520 And there are some explanations. Very frequently, those women have very high HDL cholesterol.

00:36:15.760 So perhaps some people have such an efficient reverse cholesterol transport system that they can take

00:36:22.820 care of the deposited LDL in the macrophage on the tendons everywhere. It's almost like

00:36:30.100 the reverse cholesterol transport back to the liver is so fast that you can dump anything on them. Doesn't

00:36:35.840 matter. So in other words, they have something protective. Yes, they absolutely have something

00:36:41.480 protective. And so they are almost never smokers. So if you're a man and you smoke and you have FH,

00:36:50.640 it's a death sentence. If you're not treated in the old days or people that are not discovered right

00:36:56.940 now, then really that interaction between one pack or two packs a day with LDL is the worst in terms of

00:37:04.280 heart disease risk. So the women are very rarely smoking. They also almost never have diabetes.

00:37:10.560 So they are thin, active women, have high HDLs and don't smoke. But we have desperately tried,

00:37:18.880 we even had grants and everything to understand genetically if something may be with these

00:37:23.500 people. We and no one, I think, on the planet has ever found a real good biological reason as to why

00:37:32.440 some people are so resistant against LDL cholesterol.

00:37:36.540 And I assume the sample size is not that large, but has anybody looked at monozygotic twins,

00:37:42.480 both with FH, to see if there are differences in progression as a function of various lifestyle

00:37:47.540 factors that might give us a sense of how much of that is driven by divergence in behavior.

00:37:54.880 It's very interesting, by the way, there is one of the largest monozygotic twin cohorts is in Amsterdam

00:38:00.740 at the other university. Doret Boomsma, a wonderful researcher, but FH is just too rare

00:38:07.900 to have enough of those monozygotic twins to make any conclusion.

00:38:11.720 And by the way, I'll just add something based on the discussion with Dan Rader that you referenced

00:38:16.180 that is the HDL cholesterol story is a pretty complicated story. It's a far more complicated

00:38:22.980 story than the LDL cholesterol story. The LDL cholesterol story is actually relatively straightforward.

00:38:27.380 We don't know when we measure an elevated HDL cholesterol if it is a biomarker of something

00:38:34.960 good that is happening, i.e. HDLs delipidating foam cells, macrophages, things like that,

00:38:43.300 or if it's a bad thing. I went really down the rabbit hole three years ago on the literature of

00:38:48.760 people with elevated HDL cholesterol who were developing premature ASCVD. So it posited that

00:38:55.460 these people with elevated HDLC, that was actually a biomarker for very dysfunctional HDLs.

00:39:01.220 Yeah, those are people with SRB1 mutations. Exactly.

00:39:05.520 We found one family and published that in New England. Very interesting. These people

00:39:09.260 had very high HDL, but they had premature coronary disease. But remember, the woman I'm describing

00:39:14.180 is a nice, thin, elderly grandmother who's very active, jumping up and down, doesn't smoke, 0.96

00:39:22.360 and her high HDL is definitely not a sign of something dysfunctional.

00:39:28.200 My point being is this is such a complicated, or lack of a more productive word, it's a multifaceted

00:39:36.740 problem for which there might just be in these 5% of people, again, mostly healthy women, who seem 0.97

00:39:44.780 immune to the phenotype. There's an alignment of the stars where enough other things are working

00:39:50.360 in their favor that it's offsetting this damage. So let's now talk about treatment. And I want to

00:39:56.840 talk about it through the lens of, are there any differences in how we treat people by sex,

00:40:03.840 by age, and by level of disease at time of diagnosis. So whether we're dealing with

00:40:10.400 primary prevention, and that's a term, I don't know if you would agree with me on this, but

00:40:14.840 I describe primary prevention as treatment when there is not a single discernible sign of disease.

00:40:22.020 Whereas I would call secondary prevention, if you have a calcium score of 5, we're already in

00:40:28.200 secondary prevention, even though you haven't had an event.

00:40:31.260 Or if there are abnormalities on a CTA, of course.

00:40:34.380 That's right.

00:40:34.980 No, I completely agree with you. Primary prevention is rare.

00:40:38.280 That's exactly right. So secondary prevention is, yeah, your CTA might be zero calcium score,

00:40:43.580 but there's a soft plaque well inside the artery, zero luminal obstruction, doesn't matter. You have

00:40:48.600 ASCVD that can be documented by the naked eye, effectively, not even microscopically. So we're

00:40:55.120 in the secondary prevention world. So maybe walk us through primary versus secondary prevention,

00:41:00.620 men versus women, children versus adults, and take that in any order that you like, 0.93

00:41:05.760 as far as how you think about treatment.

00:41:07.500 Okay. Let's start with the child. So the child comes to us at the age of six years is the first

00:41:15.380 time a child understands what they eat. And in heterozygous FH, it's very important to start

00:41:23.280 with a very healthy lifestyle early on. So we give them extensive anti-smoking training and we give

00:41:29.480 them extensive dietary counseling for all the good, healthy choices, and also tell them sports,

00:41:37.940 physical exercise. So there's a large, okay. But that never detracts from the fact that we will

00:41:43.340 start with a statin at the age of six.

00:41:46.460 Before you get to that, can you give some insight or color around what type of dietary advice? Are you

00:41:51.440 recommending saturated fat restriction? Because obviously saturated fats, I think in FH, you probably

00:41:58.900 have a greater likelihood of exacerbating the condition. Is it true that people with FH are more

00:42:04.880 sensitive to dietary saturated fat? Or does it just seem that way anecdotally to me?

00:42:09.840 Yeah, that's, I think anecdotally. The problem is, is that we all know that these lifestyle measures

00:42:15.940 are not going to cure FH. They are just supportive, which is very different than for the general

00:42:22.140 population, of course. But heterozygous FH is driven by the LDL and how long a patient is exposed to

00:42:29.220 that LDL. So the earlier we can intervene, the better. Actually, it's pretty clear that if you

00:42:36.060 start intervening early in LDL, you probably add 15 to 20 years to that life versus doing nothing

00:42:43.740 on the medication front. So you need to start treating the child. And of course, you start

00:42:49.040 with a statin.

00:42:49.740 Do you have a preference for statin, John?

00:42:52.720 We used to have a preference for pravastatin because it was kind of seen as the mildest.

00:42:58.580 And we were only allowed in the beginning to use pravastatin because we had done a two-year

00:43:05.720 trial where we showed that carotid IMT in these children, in a randomized trial of pravastatin

00:43:11.800 versus placebo, there was a generation of progression. So we showed already in kids between

00:43:17.500 eight and 18 years of age, that was a Yama paper, actually that we could stop the progression

00:43:23.440 of hetero when we treated them with pravastatin. And this was way back. And now there are guidelines

00:43:30.040 for the American College of Pediatrics. There are European guidelines. And in some countries,

00:43:35.380 they start at the age of eight. Other countries, it's six, but it's somewhere between six and

00:43:39.620 eight. And then you have statin. And I don't think there's much of a preference anymore for

00:43:44.000 a certain statin. Actually, some people have a preference for rosuvastatin because you can dose

00:43:49.220 it at two and a half milligram to start with, which is a tiny pill for a kid. And then you add

00:43:54.740 azinamide because you don't go to goals like you do in adults, but you try at least to have an LDL

00:44:02.540 below 130. So 130 is kind of the number. I mean, there's no, it's very interesting because there's no

00:44:08.580 intervention evidence for this at all, like in adults. You must have seen the Fourier-Olay results

00:44:15.460 that came just out two weeks ago where even LDLs below 20 are better than below 55, are better than

00:44:22.560 below 70. We don't have those data for kids. But I was going to say, I was actually kind of

00:44:27.500 surprised to hear that you would have such a modest goal of 130, given that kids without FH have LDL

00:44:36.440 cholesterol levels of 20 and 30. In other words, we know-

00:44:40.660 That's fighting conservatism.

00:44:42.460 Yes, yes, yes. No, I understand. I just want to make sure-

00:44:43.960 I don't agree. I personally don't agree with the 130, like probably you don't agree because you and

00:44:49.400 I know what the healthy LDL is for your endothelium and it's much lower than 130. But this is always a

00:44:58.220 fight where there are people that say, yeah, maybe we've done a lot of research. We've looked at growth,

00:45:03.760 mental state, at learning ability. We've looked at maturation, hormones, menarche, puberty

00:45:12.200 development, and we've never found any negative effect in kids of statins. But there are conservative

00:45:19.060 people and so we have more modest goals. But I think it's very diverse. There are pediatricians

00:45:26.020 who treat kids more aggressively.

00:45:27.700 I guess my point is it's so ironic because we have the natural experiment right in front of us,

00:45:34.420 which is kids are born with an LDL cholesterol of 10 milligrams per deciliter. And as they go

00:45:40.660 through puberty, it starts to go up. But during the most important periods of development, i.e. when

00:45:47.120 their brain is developing, that's doing so in an environment where cholesterol is virtually

00:45:53.940 undetectable. Absolutely. The first year your brain grows by far the fastest and you have basically

00:46:01.780 no LDL left to go anywhere. So it's completely scientifically agree with you. And by the way,

00:46:08.180 John, has the thinking changed with PCSK9 inhibitors? Because I guess you could make the argument,

00:46:14.020 well, statins are impairing cholesterol synthesis and maybe in a developing child that could be

00:46:22.980 problematic. But a PCSK9 inhibitor has no bearing on cholesterol synthesis. It's simply amplifying

00:46:30.020 LDL clearance. So does that change the thinking at all? Well, it changed my thinking and I agree with

00:46:38.100 you. But there are other indications, all preclinical, so pretty useless in my opinion, that in the embryonic

00:46:46.580 stage, PCSK9 has a role in brain development. And there are some Mendelian randomization studies that

00:46:54.260 pick up an increased signal for Alzheimer's disease with low PCSK9, while all the trials actually have never

00:47:02.980 shown any effect on cognition. But of course, those arguments are again used by people that are more

00:47:08.980 conservative. Listen, we have done all the trials because we have so many kids with heterozygous FH

00:47:14.820 for the files of both alurocumab, evalocumab. We've done all the trials in children for heterozygous

00:47:22.340 FH, also for simvastatin plus azidamide, all the statins alone. We've done Prava, we've done

00:47:28.580 rosubastatin, we've done simvastatin, and then simvastatin azidamibe, and then the PCSK9 monoclonals.

00:47:35.380 And so we've done all that. And the kids are, it's so interesting, kids are not statin intolerant.

00:47:42.340 Meaning you don't see kids developing myalgias and statin-related muscle symptoms at the free,

00:47:51.300 because in adults, we see that about 5% of the time. You're saying you don't see that in kids?

00:47:56.100 No. Because they don't write the inserts.

00:47:59.860 They don't read the inserts. Yeah, exactly.

00:48:02.340 Sorry, they don't read the inserts.

00:48:03.860 But do you think it's also because you're disproportionately using

00:48:07.380 prevastatin, which is milder, or do you think it's true even in the presence of rosuvastatin?

00:48:12.260 No, it's also true in the presence of atorvastatin and rosuvastatin. Yeah. And listen,

00:48:17.380 it's very interesting because we have now a follow-up, and I think that was a New England paper. We have,

00:48:23.380 of course, the kids that were 8 are now 18, 10-year follow-up, and the kids that were 18 are now 28.

00:48:33.140 So we have compared these kids with the generation above them at that age. And none of these kids

00:48:43.060 actually got a heart attack or angina or anything, and the generation above them who didn't get any

00:48:49.620 treatment, of course, because there were no statins or nothing, their early mortality,

00:48:54.820 early coronary disease was rampant. So I think we've already shown, although it's not a real

00:49:00.740 randomized controlled clinical trial, but it's the only way you can do this. You can't randomize a kid.

00:49:05.220 Of course, you can only do observational data, is that treating from an early age actually protects

00:49:11.860 the kids against premature death and premature coronary disease.

00:49:15.140 Okay. So I want to move on to another topic, but before I do, I guess the last thing I want to

00:49:21.380 contrast this with is the adult, middle-aged or otherwise, who shows up either with or without

00:49:30.180 disease. How aggressive do you go there?

00:49:33.300 We're as aggressive as the guidelines tell us to go for non-FH patients. So the kids are transferred

00:49:43.140 from the pediatric lipid clinic to the adult lipid clinic when they're 18, and then we immediately

00:49:48.580 start with PCSK9 monoclonals and pretty soon with incliceran and azitamide. And we really strive for

00:49:56.980 the lowest LDL possible for that individual. And in the homozygotes, we do high-dose statin,

00:50:04.900 azitamide, evalocumab, and now evinacumab, the Regeneron-NHPTL-3 monoclonal antibodies. So

00:50:11.780 those four things constitute the state-of-the-art therapy for homozygous FH.

00:50:17.860 It gets a lot of patients to relatively normal LDL levels. And that is a miracle for homozygous FH.

00:50:27.060 In heterozygous FH, there are about 10% of patients that even with triple therapy,

00:50:33.220 we can't get them to a reasonable LDL. So we call these now severe heterozygous FH.

00:50:39.540 which they probably have more than one mutation. They probably have another mutation somewhere else

00:50:46.980 that makes it a more severe phenotype. But that, we officially don't know that.

00:50:53.220 Meaning these patients on PCSK9 inhibitor plus statin plus ezetimibe, you can't get below

00:51:01.060 70 milligrams per deciliter?

00:51:02.980 Oh no, we don't get them below 100 or below 120. So some of them are really, they have nasty

00:51:10.900 opposition against your therapy. And it's linked, by the way, to the starting LDL.

00:51:16.740 So we say that if your starting LDL is above 300, you have severe heterozygous FH, and that's about

00:51:25.060 10% of the overall heterozygous FH population. Of course, when you start at 300,

00:51:29.940 and you have a statin that takes off 45%, and then another new baseline, 15 to 20,

00:51:36.980 and then another, then you can calculate that it's not that easy to get below 100.

00:51:42.100 Is apheresis even a viable option? Is it easy to pull out? I know it reasonably works for LP

00:51:48.020 little a, but does it work for the majority of the ApoB-bearing lipoproteins?

00:51:52.100 It does. We have an apheresis center in Amsterdam,

00:51:56.660 because we've sometimes diagnosed homozygous FH after six months, in kids of six months,

00:52:03.380 that had a very severe homozygous FH. And then we've had two LDL apheresis kids. But I can tell

00:52:10.660 you one thing, evinacumab is the golden rescue for these children. It's still only used in adults,

00:52:20.340 but I hope that we will be able to use that quadruple therapy rapidly in kids also,

00:52:25.860 because it obviates the need for DL apheresis in many instances.

00:52:31.220 What's the frequency that it needs to be given? The drug is dosed, how frequently?

00:52:35.220 It's intravenous dosing, I think, once a week. But they are working on a subcutaneous formulation

00:52:42.340 of it. Because of course, intravenous, but these kids are used to something.

00:52:46.420 Yeah. I mean, these kids don't have veins. I mean,

00:52:48.260 you're basically putting PICC lines in kids to give them treatment or something. Yeah. Wow.

00:52:52.340 So there is a small but vocal cadre of people out there who kind of refuse to believe that LDL is

00:53:03.300 causally related to ASCVD. Or another sub-variant of this group who believe that it's only causally

00:53:12.180 related to ASCVD in the context of metabolic illness. But if you're metabolically healthy,

00:53:18.100 then LDL is not problematic. Based on your knowledge and experience with FH, which spans

00:53:26.340 the spectrum of metabolically healthy to unhealthy people, how likely do you think that is?

00:53:32.580 These patients that you mentioned before are always used as the stick to beat people like me.

00:53:39.300 Because they say if LDL is truly causal, it's impossible that some people don't get heart disease

00:53:46.180 while having FH. I tried to explain that most genetic diseases are modified by other environmental

00:53:54.820 and genetic factors. But someone, these cholesterolcritics.org, it's a website of a

00:54:02.260 strange bunch of people that absolutely don't want to accept that LDL cholesterol is bad. But

00:54:08.500 my experience with FH, my entire career, I've seen these families, I've worked a hundred hour weeks

00:54:16.660 for years to find all these people. And we were able to find the largest cohort on the planet of

00:54:22.180 heterozygous FH. And these stories are all heartbreaking. So for me, it is so simple because these people have

00:54:28.180 one thing, one, a mutation in a single gene that doesn't do anything else than raise LDL cholesterol,

00:54:36.820 and they drop dead, you know, when they're like 25. So for me, I don't even listen to it anymore.

00:54:43.780 Yeah. I mean, it's the sort of Mendelian randomization also makes that clear because

00:54:47.860 it doesn't just include FH, it goes all the way down. And my response to people when they point out

00:54:53.380 the observation that there are some people with high LDL cholesterol or high ApoB who don't have

00:54:59.460 coronary artery disease is there are also people who smoke their whole lives and don't get lung

00:55:04.500 cancer. And by the way, there are people who never smoke who do get lung cancer. Neither of those facts

00:55:11.220 remotely diminishes the causal case for smoking and lung cancer.

00:55:16.900 I couldn't agree more, Peter. Absolutely. And I find it also because, of course, the FH argument was

00:55:24.980 always the scientific argument of proving that LDL cholesterol, if it's elevated, sits at the core of

00:55:32.260 atherogenesis. And then, of course, when it became clear that there were a few people among these

00:55:37.620 families who could actually live without a problem, they use that as an argument. But I completely agree.

00:55:43.380 The smoking is a very good example, but there are many more.

00:55:46.900 So let's pivot now to a class of drugs that I discussed at length with Dan Rader,

00:55:54.660 the CTEP inhibitors. Because you're very involved in not just the latest of these,

00:56:02.260 but potentially the first one that really appears to have a shot at working. So let's back up for a

00:56:09.540 second. And for folks who either don't remember the podcast with Dan or didn't hear it, let's provide

00:56:15.220 an explanation of what CTEP is and maybe a little bit of the sorted past of the CTEP inhibitors and

00:56:24.980 you know, basically, what is prologue to where you are now?

00:56:28.020 The prologue, unfortunately, is very long, Peter. And it's one of the best examples of how big pharma can make big mistakes.

00:56:37.780 So the CTEP protein was discovered by Phil Barter, the Australian KOL that's now retired.

00:56:45.540 But he discovered this protein. And I think he actually discovered it in rabbits. And why did he look in rabbits?

00:56:53.300 Because if you give a rabbit egg yolk or cholesterol, that rabbit gets atherosclerosis.

00:57:01.060 If you do the same diet to a mouse or to a rat, or a hamster for that matter, they don't get athero.

00:57:09.340 And so it was extremely interesting what made a rabbit different from other rodents.

00:57:15.240 And that is CTEP. So a rabbit has CTEP. So all strategies to lower CTEP were tested in that New Zealand white rabbit,

00:57:26.380 like siRNA, gene therapy, small molecules, antibodies against CTEP. And in all instances, you could cure the athero

00:57:37.980 with lowering of CTEP activity. At the same time, it became obvious that in Japan,

00:57:45.240 there are many people with a mutation in CTEP, so they have very low CTEP. And initially,

00:57:51.920 the first report said, these people live longer than we do, and they are free of coronary disease.

00:57:57.460 So then loss of function of CTEP became a longevity gene. It is still by many people called a longevity

00:58:04.560 gene, because if you don't have it, you live longer, you have less Alzheimer's,

00:58:10.380 you have less diabetes. And in general, you are just simply more healthy.

00:58:15.940 Sort of like PCSK9 loss of function as well. Also a longevity gene.

00:58:20.060 Yes, you don't need that. You don't need PCSK9. The theory is, is that we all went through the

00:58:28.640 evolutionary funnel about 10,000 years ago during the last ice age. There were very few humans alive,

00:58:35.800 especially in the North, and they went through the evolutionary funnel where everything was directed

00:58:41.200 against being thrifty. People that could absorb the last calorie out of a mammoth were favored.

00:58:50.560 And actually, we now think that those genes that we selected during that evolutionary funnel are now

00:58:55.820 bad for us. Like we don't need PCSK9. We don't need CETP. We probably also don't need NGPTL3.

00:59:04.320 And so all of these genes were meant to conserve energy and to conserve cholesterol.

00:59:11.180 And so what CETP does is a very simple thing is it grabs a cholesterol ester molecule from HDL,

00:59:20.080 from an HDL particle. CETP sits on the HDL particle like a little cap. It's a curved protein that sits

00:59:27.120 on top of a sphere. And it has an opening and it sucks a cholesterol molecule out of HDL.

00:59:33.900 Then that particle collides with an LDL particle and there's a little tunnel and it spits the

00:59:41.800 cholesterol ester molecule straight into LDL. So the consequence of that is, is that HDL cholesterol

00:59:48.480 goes down and LDL cholesterol goes up, which in the days of very active LDL receptor activity

00:59:56.820 was a great idea. Because then all the cholesterol went back to the liver and a cholesterol molecule

01:00:03.440 is very expensive to make. It costs 27 ATPs. In a nasty environment like the Ice Age, you want to

01:00:11.220 conserve that molecule. And the best way of conserving a cholesterol is by sending it back to the liver and

01:00:17.700 then the liver can decide what to do with it. Put it in VLDL or in bile or it can do a lot of things

01:00:23.860 with it. But in a situation where our LDL receptors are not that active anymore, adding cholesterol to

01:00:32.660 LDL is not a very good idea. And all the Mendelian randomization studies have shown that people with

01:00:40.000 high activity of CTP have more heart disease, more heart failure, more kidney disease, more diabetes,

01:00:47.580 more Alzheimer, blah, blah, blah, the whole works. And so Pfizer was the first to say, ah,

01:00:54.640 atorvastatin's patent is going to expire within a few years. Let's have another atorvastatin.

01:01:01.000 So we make a CTAP inhibitor called torcetrapib. I was involved in all these large trials. So I was

01:01:08.920 on the steering committee of the evocetrapib trial on all of these trials, except reveal that was done

01:01:14.660 by Oxford. But Pfizer did a phase two. And in the phase two, after four weeks, blood pressure went up

01:01:22.520 a little bit. And then comes the big pharma mistake. Why do we care about a little blood pressure increase

01:01:29.660 if HDL goes up by 70%? They didn't understand why the blood pressure went up and they moved the

01:01:36.880 drug into phase three. That is a fundamental mistake. If you don't understand a side effect

01:01:44.080 in phase two, you don't move a drug into phase three until you've understood it. But listen,

01:01:51.020 it was my fault also. I was on the executive committee of the outcome trial with torcetrapib and

01:01:55.320 we all thought, oh my God, this is going to be the next fantastic wave of drugs in cardiovascular

01:02:01.120 disease. But that drug killed more people than it saved. I remember in September of 2006,

01:02:08.640 exactly the street I was standing on in the financial district of San Francisco when the trial

01:02:14.860 was announced that it was being halted. And I was so, I mean, to quote, uh, planes, trains,

01:02:22.320 and automobiles, if I had woken up with my head sewn in the carpet, I would have been less surprised

01:02:28.200 than that outcome because I too was so optimistic based on the HDL cholesterol increase, even though 0.93

01:02:38.900 it was clear this trial was kind of a stupid land grab from an IP perspective on the part of Pfizer,

01:02:44.080 you know, you had to combine it with the Torvastatin and all that kind of stuff. 0.98

01:02:47.280 Exactly. Putting that aside, I thought this is going to be a world beater and it turned out to

01:02:52.540 be an enormous failure. Then everybody was fired except the basic scientists who got the assignment

01:02:59.680 to understand what happened. And they, it was so interesting because they took the drug and they

01:03:05.240 infused it into a rat. Now a rat does not have CTP, but the blood pressure went up in 10 minutes.

01:03:13.240 So that told everyone that this is a drug that has an off target effect. Fortunately has nothing to do

01:03:21.160 with CTP, but the drug actually raced straight into your adrenals where it promoted aldosterone

01:03:28.800 production, cortisol production. It raced into your endothelial cells where it promoted endothelin 0.78

01:03:35.300 one, which is like an angiotensin two, terrible vasoconstrictor. And all of that led to water and

01:03:42.160 sodium retention, low potassium, high blood pressure, because these were secondary prevention

01:03:49.060 patients. And you don't want a drug like that in a secondary prevention patient. So that was the most

01:03:55.340 unfortunate beginning of a new story in our field, the wrong drug.

01:04:00.620 You know, it's so funny. This was not too long after another epic failure, but one that I would

01:04:07.460 argue resulted in a drug being removed that shouldn't have been removed, but instead required

01:04:12.920 a little bit more work to determine who the susceptible individuals were. And of course,

01:04:16.000 that's the drug Vioxx. I don't know if it had the same name in Europe, but truly a remarkable COX-2

01:04:22.480 inhibitor in a league of its own makes Celebrex look like drinking water in terms of its impotence.

01:04:28.580 And there's no question that there were a subset of patients in whom Vioxx slightly raised blood

01:04:34.520 pressure and led to a small increase in events. But I think Merck, I think it was Merck that was the

01:04:40.640 company that made Vioxx. Again, I don't want to overspeak, but I think their arrogance and refusal

01:04:46.060 to act in a timely manner resulted in just the loss of a drug that I think to this day we'd be better

01:04:53.320 off with and without. There's just something about big pharma where they are often deserving

01:04:59.360 of the reputation they have. Not always, but often they are their own worst enemies.

01:05:06.100 Yeah. This was a prime example of how can you make such a, I mean, I'm now a drug developer myself,

01:05:13.480 so with Michael Davidson, whom I greatly admire. The idea that we would push a drug in phase three

01:05:21.100 while not understanding a side effect in phase two is just incomprehensible. And then what's

01:05:25.960 interesting, and not many people realize that, Peter, then came Roche.

01:05:29.920 Yes. And this is what? This was a dulcetrapib.

01:05:33.340 Dulcetrapib. Yeah.

01:05:35.440 Dulcetrapib. That drug was extremely important for all the science because that drug only raised HDL.

01:05:42.320 It was a very weak CTP inhibitor. It only raised HDL by 30%. And there was no effect

01:05:50.140 on the Kaplan-Meier curve in the cardiovascular outcome style whatsoever. And what people didn't

01:05:55.080 realize, that drug was the end of the HDL hypothesis because there was no effect on LDL,

01:06:01.800 no effect on FOB, no effect on non-HDL, but there was a 35% raising of HDL cholesterol. And that

01:06:08.900 did not translate into one less heart attack or stroke. So that ended the HDL hypothesis in a way.

01:06:16.720 Yeah. And I think we would only go on afterwards to see two Mendelian randomizations. One looking at

01:06:23.960 genes that raised HDL cholesterol, one looking at genes that lowered HDL cholesterol, neither were found

01:06:30.640 to be causally linked to ASCVD. So when I hear people tell me that their high HDL cholesterol

01:06:37.660 is protecting them from coronary artery disease in the presence of high LDL cholesterol, I have to

01:06:43.980 restrain myself in the context of CTEP inhibitor failure number 1, 2, 3, 4, 5, 6, 7, and Mendelian

01:06:51.920 randomizations that, as you said, completely fly in the face of this hypothetical belief system.

01:06:58.640 But what is extremely interesting is that in those days, we didn't understand that you really need

01:07:06.240 to lower LDL cholesterol with a CTP inhibitor to see an effect on ASCVD. So Merck then actually was

01:07:15.480 the third, they got a drug called Anacetrapib. And by that time, people weren't sure anymore whether

01:07:22.340 they had to power an outcome trial on the basis of the HDL cholesterol increase or the LDL. And Merck

01:07:29.200 said to Oxford, just make the trial large enough. And they did a 30,000 patient trial, which is,

01:07:36.520 I think until now, still the largest cardiovascular outcome trial ever. 30,000 patients. But

01:07:43.680 they overestimated the LDL lowering. The drug only lowered LDL by 17%. The baseline LDL in that trial

01:07:54.380 was 60 milligram per deciliter. So the absolute LDL was 11 milligram per deciliter. That predicts,

01:08:01.820 if you put it on the matter regression line, that predicted a 9% reduction in MACE, and that's exactly

01:08:08.860 what they got. So that trial validated that CTP inhibition only lowers heart attacks by virtue of

01:08:16.860 its LDL lowering, and that it answers to the same law as statins, azitamide, and PCSK9 monoclonals.

01:08:26.100 It is on the same regression line. So then Michael and I understood that what we needed to find was a

01:08:34.880 CTAP inhibitor that didn't have the off-target effect of torcetripib that was way more potent than

01:08:41.300 dolcetripib and lowered LDL robustly so we could repeat the anacetripib trial, but then with a much

01:08:48.920 bigger effect size. And we found that drug at Mitsubishi. Before we talk about obacetripib,

01:08:55.560 I want to kind of highlight two things you said. The first is you have literally provided the most

01:09:02.240 lucid evolutionary explanation for our species-wide transition to the preservation of ApoB. I have to

01:09:14.100 be honest with you. I had never heard it explained the way you did, and it makes so much more sense

01:09:19.860 than any other kind of teleologic or evolutionary explanation. So I just want to make sure I heard

01:09:25.480 it correctly because I'm going to use it often. I'm going to be the most boring guy at the parties now

01:09:30.820 because I'm going to use this story to explain it. It's called the thrifty gene hypothesis,

01:09:38.500 and it's more often used to explain, for example, that people in Asia get type 2 diabetes at a much

01:09:47.620 lower BMI than we Caucasians because they've gone through much more famine. When the rice failed,

01:09:56.600 huge famine in the Far East. Yeah, and I've always been familiar with those arguments as they pertain

01:10:03.160 to diabetes and obesity. I just had never taken the additional leap of, hey, I know it takes 27 ATP to

01:10:12.480 make a molecule of cholesterol, but I never made the additional leap, which was, think about how

01:10:18.120 expensive that is. And in an environment that is so resource-constrained, which up until 150 years

01:10:24.760 ago, we were. So we spent hundreds of millions of years in an environment where preservation of

01:10:31.560 resources was the second priority only after reproduction, that of course we would be so effective

01:10:41.000 at LDL clearance. And therefore, of course, we would want to be in the business of shuttling as much

01:10:50.460 cholesterol from HDL into LDL via RCT because we knew it was going to a good place. Back to the liver,

01:11:00.060 it would be circulated as bile. We would ultimately recirculate that pool. We could make more hormones.

01:11:05.120 We could digest more food stuff. Yeah, it all makes sense. And then lo and behold,

01:11:09.800 about an effect of like 150 years ago, it was not such a premium on that now. And we've got

01:11:14.400 more than enough cholesterol to spare. And that thing, that gene that we worked for millions of 0.78

01:11:20.420 years to preserve now is biting us in the ass, just like the same genes are around adiposity and 0.97

01:11:27.380 insulin resistance. And there's a very interesting additional piece of evidence is that if you make 0.96

01:11:33.240 a mouse look like a human heterozygous FH and you infect that mouse with the bacteria and compare

01:11:40.980 the results of infection with bacteria in the non-FH mouse, the FH mouse is better resistant

01:11:48.200 against bacterial infection. And so the theory is, and we've seen that in our pedigrees, is that FH

01:11:55.220 in 1860 was not such a severe disease as it's right now. And maybe there is so much FH because

01:12:05.480 again, in the ice age, having high LDL might have been an advantage as a protection against bacterial

01:12:14.220 infection. These two things converge. Yeah. And think about how amazing that is in terms of a

01:12:20.380 parallel to APOE4. Exactly. Like this is the exact same story as APOE4, which basically was the only

01:12:27.920 APOE isoform we had until what, 200,000 years ago? Yeah. Something like that, I think. Yeah. And

01:12:33.920 it offered remarkable protection against infections. And of course, it's only today,

01:12:41.180 A, with our longer life, but B, I would argue with all of the insults that come with our longer life,

01:12:47.300 that APOE4 is such a predisposing factor to both cardiovascular and neurodegenerative risk factor.

01:12:53.760 Okay. So first off, that was an amazing explanation of the story. So that was actually also, I think,

01:12:59.480 a fantastic prologue for those who missed the discussion with Dan. So let's recap where we are

01:13:05.900 with Obacibitrib, right? That's the current one? Yes.

01:13:09.620 So it is how potent? I guess you've done phase two. Yeah. I don't, listen, I am still a scientist

01:13:16.400 and I don't want to sound like a salesman, but we were lucky finding this drug in Mitsubishi.

01:13:23.580 Yeah. So tell us more what that means. So help folks understand how do you find a drug? How is

01:13:27.420 drug discovery done? How did this thing come about? So I am a consultant to many biotech companies and

01:13:34.240 sometimes companies ask me to look at the pipeline and see if there's anything good or bad in it.

01:13:40.400 So I was invited by Mitsubishi to look at a number of things. And I saw the phase one data of this

01:13:47.100 compound that was still called TA-8995. And I saw that at one milligram, that drug lowered LDL by 27%.

01:13:56.020 Now, remember, Dulcetripib was used at 600 milligram and it didn't do anything on LDL. So I thought,

01:14:05.920 holy moly, this drug is very potent. And then I looked at the CTP inhibition at 10 milligram,

01:14:12.960 which is a dose we're now using. There's a 97% inhibition of CTP. So it's simply in that sense

01:14:20.140 and surprisingly potent CTP inhibitor. And that translates into an LDL lowering of about 50%

01:14:28.260 on top of high intensity statins and an HDL increase of 165%. Now, you have to control yourself when you

01:14:38.400 see those numbers, because you know that the HDL cholesterol increase is not going to do anything

01:14:45.240 for heart attacks and strokes. But Michael and I are not only working on this drug to develop it,

01:14:52.460 we're also scientists. And we wanted to understand all the genetic and epidemiology and Mendelian

01:14:58.980 randomization data. And so we've gone far beyond heart disease with this drug. We're looking at

01:15:06.360 Alzheimer, age-related macular degeneration, septicemia, and diabetes. Because

01:15:14.600 if you really inhibit CTP, you not only stop the transfer from cholesterol from HDL to LDL,

01:15:24.620 but you completely change lipoprotein metabolism and you force the liver to produce more EPO-A1.

01:15:33.560 And you and I can, I think, agree on the fact that EPO-A1 is a fantastic molecule,

01:15:38.820 because it is the molecule that ABC-A1, the cholesterol pump on the cell membrane, recognizes

01:15:46.780 and actually exports cholesterol to. So that was a first. And then we also know that if you produce

01:15:54.880 lots of EPO-A1, you produce lots of pre-beta HDL particles, the small HDL particles. And these

01:16:02.000 particles suck cholesterol out of peripheral tissues. Now, in endothelial cells and macrophages,

01:16:08.980 that's probably good. But what's much more interesting is that they suck cholesterol out

01:16:13.740 of the beta islet cells in your pancreas. And you undoubtedly know that with life, if you're a type

01:16:21.640 2 diabetic, more and more of these cells die till the point that you become insulin-dependent.

01:16:27.180 That is because of the lipotoxicity of that cell. That cell takes cholesterol, can't export it.

01:16:35.460 The sterols are oxidized. They become pro-inflammatory, toxic. The cells go into apoptosis

01:16:41.160 and they die. So that is all. And this is proven now for all four CTP inhibitors. So all four CTP

01:16:49.560 inhibitors in their outcome trial had less diabetes in the treatment arm than in the placebo arm. And we've

01:16:55.640 published that in a meta-analysis about half a year ago. Just to be sure I understand, John,

01:17:01.280 is that because you think regardless of which of the CTP inhibitors we saw, we were seeing more

01:17:07.760 heterotypic exchange between the APO-Bs and the APO-Ns? Okay, so let's explain for people.

01:17:14.560 Tell them the difference between homotypic exchange and heterotypic exchange, which is pretty easy to

01:17:20.520 define, but more importantly, clinically, where these are occurring and why these are leading to

01:17:26.800 the outcomes that we're about to get into. So the sequence is probably this. You stop the transfer

01:17:35.800 of a cholesterol molecule going from HDL to LDL. That will make HDL higher, by definition, and LDL

01:17:46.440 lower. Now, Dan has done stable isotope turnover studies and have shown that the reason for the lower LDL

01:17:58.440 is that they are sweeped up by the liver. So these LDLs actually get 50% lower, which is a huge drop

01:18:08.860 because the liver upregulates, and what can the liver upregulate? Their LDL receptors.

01:18:16.020 At the same time, these large HDLs take EPO-E on board. And as you know, EPO-E is also

01:18:23.580 a ligand for the LDL receptor. So the large HDL particles are also cleared by the liver.

01:18:30.520 And the liver does that because it produces large amounts of EPO-A1, which kind of disturbs the

01:18:38.360 balance. So there is a new equilibrium between removal of lipoproteins by the liver and production

01:18:45.480 of small HDL particles. But that only happens if you almost completely knock out CTP. So you have to

01:18:52.360 really inhibited by about 90%, which is very close to the homozygous patients in Japan.

01:18:59.140 They also have half LDL and about a triple HDL and every other thing that I just described.

01:19:08.100 So it's for me, and I think also for Tom Dayspin and people that really know lipids, this is extremely

01:19:14.440 interesting because it is complex. It is complex, but until now, it is extremely exciting because

01:19:23.600 there are two groups in the world. So this is the diabetes part, you know, where you suck cholesterol 0.93

01:19:28.400 out of the beta cell. Then there is the septicemia part that I never really knew about. There are two

01:19:34.040 groups in the world, one in Vancouver and one in Leiden that have shown that if you're born with

01:19:40.100 a loss of function variant in CTP, you are much better protected against septicemia. And not a

01:19:46.620 little bit, but like mortality, big effect. Actually, there are multiple presentations this

01:19:52.120 year of these two groups. And they, of course, want our drug to test it in septicemia.

01:19:57.600 Let me make sure I understand something. And I want to go back and ask a question about FH to

01:20:02.680 bring it back to that. Is there any evidence that FH patients untreated have a lower mortality

01:20:08.580 due to septicemia?

01:20:10.540 It's not great science, but there are some indications, but most of that work is done

01:20:15.860 preclinically.

01:20:17.380 So it's not as straightforward as, look, if you have high peripheral cholesterol, you have more

01:20:25.960 precursor to make corticosteroids and therefore support immune function in the time of sepsis.

01:20:36.140 It's much more complicated than that.

01:20:38.700 No, it's way more complicated. And it's most likely has to do with the scavenging function

01:20:44.440 of lipoproteins. So if your CTP is low, when you get septicemia, your HDL stays high. And it's very

01:20:54.260 likely that the HDL particle functions as a sink for endotoxins and everything else. And so having a

01:21:02.860 high HDL and a constant high HDL during septicemia is a very good thing.

01:21:08.780 And I, on a recent podcast, shared that I used to witness the opposite in the ICU, which was a drop

01:21:15.940 in HDL cholesterol.

01:21:17.440 Yes, you always witnessed that.

01:21:18.660 Yeah. And that would actually be a poor prognostic indicator. Not necessarily poor,

01:21:23.340 it's just that's the normal indication. Yeah, yeah.

01:21:25.640 Yes. If your HDL drops light to nothing, that's a poor prognostic indicator.

01:21:30.540 You are protected against that drop if your CTP activity is low, because it's like having a CTP

01:21:38.280 inhibitor on board, which stops removing cholesterol from HDL.

01:21:42.920 Yeah. So again, this is a function issue that is not just a blind phenotype issue. The sort of

01:21:49.920 paint-by-numbers approach to this problem is high cholesterol good because it's more precursor.

01:21:56.100 No, no. It's CTP inhibition good because you have a bigger sink to dispose of toxic waste.

01:22:04.080 Absolutely. That's it. So that is the septicemia part and the diabetes part. Now, the diabetes part

01:22:13.620 is proven in a meta-analysis. For example, the Roche drug, and that's so interesting, the Roche drug

01:22:20.080 only raises HDL.

01:22:22.560 Doesn't lower LDL.

01:22:24.240 No, zero. And so its protective effect against diabetes can only be connected biologically with

01:22:31.240 the HDL, of course. And so it's now thought that if you raise HDL with CTP inhibition, you

01:22:37.560 protect the bronchiose against apoptosis. It's an effect of about 16 to 20% in the new onset

01:22:46.260 type 2 diabetes between placebo and active treatment arm. So it's not like a tiny effect. It's almost

01:22:52.280 as big as the negative effect of statins on diabetes, which is also at the highest dose, 15%

01:23:00.540 or so.

01:23:01.980 So let's just make sure, again, we bring it back to this idea, because am I correct in

01:23:06.020 saying that obocetrapibs, the first CTP inhibitor that impacts both heterotypic and homotypic

01:23:14.980 exchange?

01:23:16.480 That is very hard to say, Peter, because there is not much work done with the older CTP inhibitors.

01:23:24.540 Dan Rader has done a huge amount of work with the Merck and the cetripib. He has, for example,

01:23:29.980 shown that HDL particles from anacetrapib-treated patients have more cholesterol efflux from

01:23:36.840 macrophages. He has shown that SRB1 is upregulated in the liver by CTP inhibition with that drug.

01:23:44.580 So he has done a lot of that work with the other drugs. Not so much. Not so much.

01:23:50.280 Okay. This is pretty exciting. A sort of student of this world would have to be forgiven for having a

01:24:00.900 little bit of anxiety and fear about being too optimistic here, right? This is one of those

01:24:06.640 things where we've been burned on every one of these, right? There's a track record of four or

01:24:13.620 five consecutive failures, some more epic than others, perhaps none more epic than Pfizer's.

01:24:20.820 And yet, let's just say like if you were a Wall Street analyst trying to get your arms around this,

01:24:26.540 you'd have a really hard time getting excited based on how many times you've been burned.

01:24:31.320 But we're not stock analysts and we're really just trying to come at this through the lens of

01:24:35.500 science. What would you say is the greatest risk that this does not pan out? So let's explain what

01:24:44.440 has, what we know so far. You've completed phase one. So there's no, there's no toxicities.

01:24:48.900 And phase two. We've also completed phase two.

01:24:51.260 And you had four phase two trials?

01:24:53.460 We have one, two, three, four phase two trials. Yes. And we are now fully in phase three. And in fact,

01:25:00.520 all our phase three trials will be fully randomized this year. So we have gone, we've pulled every

01:25:08.040 plug we could. We've started the outcome trial at the same time as our lipid trials, because we

01:25:13.900 of course realize that what we need to show is robust LDL lowering, robust non-HDL lowering,

01:25:21.740 robust APO-B lowering. And then we need to show safety. So blood should be no blood pressure effects,

01:25:28.320 nothing, good safety, good tolerability. It's a tiny pill, a 10 milligram pill. And then of course,

01:25:34.240 at the end of the day, we also need in the future to show outcomes in a cardiovascular outcomes trial,

01:25:39.720 of course. But I have to say that until now, Peter, this drug is well tolerated. We haven't seen any

01:25:47.020 side effects in phase two. And it lowers LDL by half, which makes it just as potent as the injectables.

01:25:54.600 But then in a 10 milligram pill, when we first saw these LDL results on top of high intensity statins,

01:26:01.960 I was kind of amazed at this. Yeah. So I don't want to get too far ahead of ourselves,

01:26:07.440 but I'll just assert something here, which is if this pans out to be as good in large phase three

01:26:14.680 studies as it has been in phase two, the only thing that would stand in the way of this displacing

01:26:21.380 every statin on the planet is cost. Because you'd have equal or better lipid lowering efficacy.

01:26:29.560 And instead of having a small increase in the risk of type two diabetes, you would be patently

01:26:35.260 reducing that risk. We're going to talk about the brain in a moment as well. There may even be some

01:26:40.480 benefits there, but let's put that aside for the moment. So there's a lot riding on this.

01:26:45.320 It's cheap, Peter. It's very cheap to make.

01:26:47.920 Well, I was going to say, given that it's not an injectable monoclonal antibody, this-

01:26:51.420 Yeah, it's cheap to make. And yeah, it's actually very cheap to make. I think this is public

01:26:56.560 knowledge. It will cost $36 per year to make this drug at the time when you have lots of patients. So

01:27:04.920 what's called peak sales. So the drug is cheap to make, and that will allow us to price it

01:27:11.980 reasonably and ethically. And that is something that Michael and I have always wanted,

01:27:18.660 is to have a drug that lowers LDL that you can use on top of statin or in a fixed dose combination

01:27:25.440 with azitamide that robustly lowers LDL and ApoB, has little or no side effects, and is easy to put in

01:27:33.540 your pillbox. Because the vast majority of my clinic in Amsterdam, they have pillboxes.

01:27:39.040 And they are a bit afraid of a needle, and they want an extra pill to get their LDL down.

01:27:45.380 So let's talk about the three trials. Just to be clear, the three, phase three trials,

01:27:50.900 you have Broadway, Brooklyn, and Prevail, right? So Broadway is 2,400 patients one year.

01:27:57.200 It's looking at drug-

01:28:00.720 ASCVD patients.

01:28:02.080 So these are high risk. So this is secondary prevention in people who are on their existing

01:28:08.400 maximally tolerated lipid-lowering therapy, and you're going placebo versus drug. It's not open

01:28:14.640 label, correct? Yep.

01:28:15.960 No, no, no. It's placebo-controlled, two-to-one randomization.

01:28:19.000 And is the belief that this trial in 52 weeks with 2,400 patients is significant enough to

01:28:26.000 see a difference in MACE? Or is this not powered for MACE, and it's just a biomarker study?

01:28:30.640 No, it's not powered for MACE. But of course, every phase three trial, whether you've alirocumab,

01:28:36.800 evalocumab, incliceran, or even bampidoic acid, we are adjudicating events. We expect about 120

01:28:45.260 events in its entirety. And of course, we hope to see a trend. That's what you hope.

01:28:51.400 Yeah. So in other words, rather than 80-40 between your two-to-one randomization,

01:28:55.560 there may be a significant difference, although you're not really powered to it unless

01:28:59.440 the difference is significant.

01:29:01.200 We are not allowed to do statistics. The FDA does not allow to do statistics,

01:29:05.360 but this is just descriptive. And exactly like incliceran, incliceran had about a 30% difference

01:29:12.580 in events if I remember correctly. And that at least gives you an indication that it's moving

01:29:19.000 in the right direction. So everyone hopes for that, of course.

01:29:23.540 Okay. So then you've got Brooklyn, which is a very small trial, but it's also-

01:29:27.100 FH.

01:29:27.380 Yes, exactly. That's in heterozygous FH, 300 patients, same thing.

01:29:32.180 Same thing.

01:29:32.720 And then prevails the big one, right? So that's where you've got 9,000 patients. And

01:29:39.120 are these people with existing ASCVD as well? So it's also secondary prevention.

01:29:46.060 Yes. It's hardcore ASCVD. And we've even entered a lot of risk-enhancing factors into this trial.

01:29:55.160 Because we understand that the higher the risk, the easier it is to show a benefit. And we also

01:30:01.700 strive for a baseline LDL of around 100. Because if your baseline LDL is around 100 and your LDL

01:30:10.100 lowering is 50%, then your absolute difference is 50 milligram per deciliter. If you plot that

01:30:17.260 on the CTT metoregression line, you have a 27% MACE reduction, which of course you can't do because

01:30:26.440 there will be people on off-drug, there will be people who are going to take a PCSK9 monoclonal.

01:30:33.740 But at least we are very sure that it's going to be more than 20% MACE reduction.

01:30:40.960 And aside from not having coronary artery disease, what are the exclusions for Prevail?

01:30:47.260 If your LDL is below 55 milligram per deciliter. So we have adapted Prevail to the new American

01:30:53.940 College of Cardiology guidelines. So one of the things that I've talked about,

01:30:58.780 I think on this podcast, is that when Fourier and Odyssey were launched, especially Fourier,

01:31:06.760 I was personally quite skeptical. Not because I didn't believe PCSK9 inhibitors would work. I

01:31:12.240 really believed PCSK9 inhibitors were going to be a home run. I believed that they were going

01:31:17.160 to be incredibly safe. So all these things that ended up being true, I actually believed,

01:31:21.860 but I thought the trial would fail because the patients were coming in. This was also secondary

01:31:28.860 prevention. So a very similar patient population to Prevail. These people have an average LDL

01:31:33.880 cholesterol of something like 70 milligrams per deciliter on the way in. So you're taking

01:31:37.820 people who are heavily drugged to LDL cholesterol of 70 milligrams per deciliter,

01:31:43.040 randomizing them to PCSK9 inhibitor versus placebo. My thought was you can't do that study long enough

01:31:49.360 to see a difference. Well, I turned out to be completely wrong, right? That study was halted

01:31:54.000 at something like 3.2 years. But do you worry about that risk here, which is you've got patients

01:32:00.900 that are so heavily medicated. Yes, you're going to exclude them if they're down at 55, but look,

01:32:06.580 you're going to have a lot of people at 70 milligrams per deciliter.

01:32:09.260 Yeah, but it's interesting is that we have already randomized a very robust number because we expect

01:32:14.740 to be ready before the end of the year with 9,000. So you can imagine that we already have a

01:32:19.080 substantial amount of people and baseline LDL is still exactly where we want it around 100

01:32:25.400 because we have actually kind of promoted the inclusion of high LDL patients into our trial,

01:32:32.860 in our discussions with the sites and everything. And what was another very big mistake of Fourier was

01:32:40.860 that it was not 3.2, but it was 2.3 years. Oh, gosh. I got my numbers mixed up and it becomes even

01:32:48.400 more. Yeah, it doesn't matter. It does a 2.3 and that was too short. That was too short. So we've said

01:32:55.200 after our last patient goes in, we at least want to have a two and a half year follow-up.

01:33:03.380 So that determines that your trial, because of course, everyone before that already has follow-up

01:33:10.180 and then you add another. So we think that we'll have a median follow-up of three and a half to four

01:33:15.640 years, and that's really long enough to see the full effect of lipid lowering. Is Prevail being run

01:33:22.480 in Europe and North America? Yes, absolutely. Canada, North America, South Africa, Europe,

01:33:28.460 Eastern Europe, Western Europe. Any other side effects show up in phase two? Obviously,

01:33:34.220 you're not seeing insulin resistance. You're not seeing any muscle soreness, any of the typical

01:33:38.340 statin-related side effects. Any GI side effects, anything, or is this truly a- Zero.

01:33:43.120 I hate to sound like a salesman. We have a paper in the Nature Medicine, Lancet, and we are submitting

01:33:52.420 our ROSE2, which is our fixed dose combination with azitamide to another very good journal.

01:33:59.100 And so you look at the tables, there are no side effects. We have not identified a single side

01:34:04.780 effect related to study drug until now. Now, of course, that will change because in phase three,

01:34:09.500 the numbers are bigger. But in phase one and phase two, we have seven phase one studies and four

01:34:14.060 phase two studies. There's nothing. By the way, which was also true for the Lilly CTAP inhibitor,

01:34:21.820 the ROSE CTAP inhibitor, and the Merck CTAP inhibitor, there were none of these three had

01:34:27.380 side effects. 60,000 patients in outcome trials. So the drugs, if you discount the Pfizer misery,

01:34:34.940 the rest of them was very safe. Yeah. So in that sense, from a side effect profile,

01:34:41.420 we're really moving into a world where between bempendoic acid, ezetimibe, potentially

01:34:48.260 obisetripib, and PCSK9 inhibitors, you're talking about a class of drugs that don't have side effects.

01:34:55.760 It's really the statins, which obviously do have side effects, although in relatively fewer people

01:35:02.120 than is generally perceived, that kind of give the overall class a bit of a bad name in terms of

01:35:08.220 side effects. Yeah, there's still, you know, books out there like the cholesterol myth and statins are

01:35:14.400 toxic. And it's interesting because in people that really need it, like severe heterozygous FH,

01:35:22.540 you see a lot less statin intolerance than in people in primary prevention that just

01:35:28.040 have it as a lifestyle drug. So there is a large psychological component to all of this,

01:35:33.900 undoubtedly. So do we see any benefit on LP little a reduction?

01:35:42.460 We do. How much? 56%.

01:35:46.100 Oh, so more than with a PCSK9 inhibitor then?

01:35:50.380 Yes. Okay. So say more about that.

01:35:55.620 So again, Dan Rader, you know, he's my lifesaver. So Dan did a stable isotope study with anesetripib

01:36:03.540 and found out that that CTP inhibitor inhibited the synthesis of EPO little a.

01:36:11.240 Now, how that is possible, I have no idea at all, because I cannot connect an intracellular synthesis

01:36:22.040 of a protein to a drug that sits on an HDL particle in your circulation. So there must be

01:36:29.780 a link that we still don't understand. So he, but he, that was a stable isotope study published in a good

01:36:36.240 journal. He's going to do all of that again for us. So we are going to do a stable isotope study

01:36:42.000 with Dan for EPOB containing lipoproteins, and we're going to look at EPO little a. But in our

01:36:48.960 ROSE trial, which was, you know, the Nature Medicine publication, LP little a went down by 56%

01:36:55.540 of the 10 milligram dose and 43 on the five milligram dose. What's interesting is that other CTP inhibitors

01:37:03.860 lower LP little a by about 20%, but they are about one third of our efficacy. So it feels like the LP

01:37:14.260 little a lowering is in conjunction with the LDL lowering. But again, sorry, Peter, I, I'm, I can't

01:37:24.260 explain this. I can't. No, no, it's amazing. And of course, for those listening with elevated LP little

01:37:29.460 a, which of course is hands down the most common genetic finding that leads to premature ASCVD.

01:37:36.580 I mean, if we know that there are a few thousand people that are, you know, listening to this who

01:37:40.820 have FH or some trait, there's tens of thousands listening who have elevated LP little a. As impressive

01:37:47.620 as a 50% reduction is, we don't yet know if that's clinically enough to reduce outcomes. And that's

01:37:53.820 where I still think I have not had Sam Tamikas on the show, but remains to be seen if the ASO inhibitors

01:38:00.600 will be the lifeline there. So I think that we'll have to put a TBD pin in that. I want to go back to

01:38:06.760 something else that we didn't talk about, but I want to just remind the audience of the Mendelian

01:38:13.540 randomization. So we go back to the observation, which is that CTEP activity is largely genetic.

01:38:23.460 And we've already talked about the fact that there are some people who basically are CTEP

01:38:30.500 hypo-functioning individuals. These people tend to live a very long life. They have less heart disease,

01:38:36.900 they have less Alzheimer's disease, they have less diabetes, less heart failure, and less renal disease

01:38:43.500 also. Oh, I didn't know about the renal disease. Okay. So we basically say, look, in addition to

01:38:48.760 APOE2 as a longevity gene, FOXO, APOC3 hypo-functioning, we can now add hypo-functioning CTEP

01:38:57.260 to the list of things like hypo-functioning PCSK9. When you go and look at the MR, the Mendelian

01:39:02.920 randomization, it makes it very clear that for every one microgram per milliliter decrease in a

01:39:10.520 genetically determined CTEP concentration, we're going to see about a 0.1 millimole per liter

01:39:18.760 reduction in LDL-C, about the same reduction in triglyceride, this enormous 2 plus nanomole per

01:39:26.760 liter reduction in LP little a, the 0.2 to 0.25 millimole per liter increase in HCL cholesterol,

01:39:33.300 et cetera, et cetera. But one of the things I never realized was you're also seeing a reduction in

01:39:37.540 blood pressure, about 0.2 millimeters per mercury, which again, doesn't sound like much until you

01:39:43.800 realize that this is just normalized to one microgram per milliliter. You also see a 0.1 roughly millimole

01:39:51.000 per mole change in hemoglobin A1C. In other words, this is a potent antihypertensive agent as well.

01:39:58.240 What in the heck explains that? Yes. So there's absolutely no explanation for that. It was, by the

01:40:07.540 way, very interesting because those data on blood pressure were already known at the day of

01:40:13.400 torsotropib. Which should have been a red flag to these guys, right? Exactly. Which should have been a

01:40:18.680 double red flag to these guys that if you inhibit CTP, you can't, the blood pressure increase has to

01:40:25.360 come from something else. Okay. But no, no one understands the blood pressure at all. There's

01:40:30.020 no, because CTP is made by the Kupfer cells in the liver and it gets synthesized, excreted. It sits on

01:40:39.920 the back of an HDL particle. One in 10 HDL particles have a CTP protein on their backs. And the half-life

01:40:48.960 is actually the half-life of an HDL particle, which is about a week. So it's a very simple protein.

01:40:55.180 It sits in your circulation or an HDL does what it needs to do. And how on earth it can have anything

01:41:01.260 to do with blood pressure, I would surely not know. The relation with brain lipid metabolism,

01:41:07.560 there's much more known about that now than, let's say, two years ago. So there, we're making

01:41:13.360 great strides in understanding how loss of function of CTP influences brain cholesterol metabolism.

01:41:22.820 That's fantastic science. So I know I promised you that I wouldn't keep you up too late in the

01:41:29.040 evening in Amsterdam, but I just don't see how we can end this podcast now without going down that

01:41:34.380 rabbit hole a little bit. Would you grant our listeners a little bit more of your precious

01:41:37.840 time that you've been generous in sharing? Okay. Thank you, John.

01:41:40.560 So if you look at late-onset sporadic Alzheimer, which is the vast majority of Alzheimer patients,

01:41:48.440 65% have an EpoE4 molecule on board. They're either E4E4 or E3E4 or E2E4. So they have an E4.

01:41:59.320 If you have E4E4, your risk for Alzheimer's is 16 times higher than when you have E3E3. And if you

01:42:06.740 have E3E4, your risk is about four and a half times higher. We now begin to understand why

01:42:13.140 carriership of EpoE4 is so bad for the brain. EpoE4 is an insufficient molecule to get cholesterol

01:42:23.140 out of cells in the brain that have too much or bring cholesterol to cells in the brain that have

01:42:29.280 too little. So it fails on both accounts. It is not a good acceptor of cholesterol and it's a bad

01:42:37.000 bringer of cholesterol. And so if you are E4 and those cholesterol abnormalities accumulate over life,

01:42:46.380 you actually get sterile accumulation in neurons. And if you have sterols in a cell too long,

01:42:54.980 they get oxidized. I mean, everything oxidizes in us. We rust. Like anything else, if we are exposed

01:43:02.160 to oxygen, we get oxysterols. Oxysterols are what kills cells. It gives a pro-inflammatory signal.

01:43:11.280 It drives cells into apoptosis. It is the worst thing that you can have. Now, an oxysterol is not

01:43:17.980 much of a problem if you have a functioning particle in your brain that sucks the sterols out of the cell

01:43:24.760 and then converts it to 24-hydroxycholesterol and that gets through the blood-brain barrier to your

01:43:31.220 liver, up into bile, and it's gone. That whole normal process where the brain needs a lot of

01:43:37.840 cholesterol for myelinization, building synapses, building these sprouts, and at the same time,

01:43:45.560 if they have too much, they want to get rid of it fast in order not to get, is all wrong in an

01:43:50.440 ApoE4 carrier. So what is the protein that can help here? It's only one protein, ApoA1.

01:43:59.080 ApoA1 can take over all these functions of ApoE4. And how do you get ApoA1 in the brain?

01:44:08.900 By raising it substantially in the circulation. Because unlike ApoE, ApoA1 can get through the

01:44:16.080 blood-brain barrier because it's small enough and there's very likely a specific receptor that

01:44:22.660 actually pushes it through brain cells. And which drugs do raise ApoA1 by far the most? CETP

01:44:31.460 inhibitors. So that is the connection. So these large HDLs, they acquire ApoE because they get larger

01:44:40.620 and they lose their ApoA1. And we think, and we have preclinical, already some evidence for that,

01:44:47.560 but we're doing a trial in humans where we tap CSF to look at ApoA1, that if your ApoA1 concentration

01:44:54.980 goes up in the circulation enough, you'll push it into your brain. And once it's in the brain,

01:45:01.040 it takes over the function of this dysfunctional ApoE4. It's a fantastic story, Peter.

01:45:07.240 The nomenclature makes this complicated. So I guess let's make sure people understand what

01:45:12.280 we're talking about. It's always a problem when the gene and the protein have the exact same name,

01:45:18.520 right? At least with Lp little a, we have the Lpa gene and then Lp little a, the lipoprotein. But here,

01:45:26.740 it's the same name. We denote it differently, right? We use all caps versus not and italics and all that.

01:45:31.760 But when we talk about the ApoE4 gene having these three isoforms, 2, 3, and 4, you're going to get

01:45:39.520 six different combinations of them. But what you're talking about is the protein. You're talking about

01:45:44.260 the thing that is made by the gene. Again, what's just another remarkable insight into the complexity

01:45:50.460 of biology is the protein ApoE, which is not designated 2, 3, or 4. It's just the protein ApoE.

01:45:57.540 The one that is made, that is transcribed and translated by the E4 isoform, I believe it only

01:46:05.120 differs in one amino acid from the wild type. It's a very subtle difference, right?

01:46:10.260 It is. It is an arginine for a glutamine, I think, or something at amino acid 152 or 118. I can never

01:46:17.040 remember it.

01:46:17.420 I always thought it was 127. So yeah, one of us is wrong, but yeah, whatever.

01:46:21.040 Yeah, well, I'm sure I'm wrong. It's only one amino acid. And that changes the three-dimensional

01:46:28.580 conformation of that protein completely and makes it basically a lousy cholesterol acceptor

01:46:35.940 and transporter. If you carry an E4, you have like a list this long of things that go wrong

01:46:42.800 in your brain. It's pro-inflammatory. It is insufficient in lipoprotein metabolism.

01:46:48.800 It is no longer a chaperone for beta amyloid. You know, it's like a very long list and it's

01:46:55.040 terrible for people that have E4. I think one of these Hollywood actors actually knows that

01:47:01.460 he is an E4 carrier. He's that athlete.

01:47:05.180 Chris Hemsworth. Yeah, he disclosed this during the Limitless series, which I think was really

01:47:11.000 valuable for a lot of people to see, to bring a lot of awareness to this. And by the way, I've

01:47:16.020 made the point many times that it is very valuable for someone like Chris to know that he has APOE4

01:47:24.440 because the earlier you take steps to prevent the exacerbating risk factors, the better your odds.

01:47:33.040 I mean, the one thing that's important to point out, you opened this discussion by explaining

01:47:36.880 the risk factors. I look at data that suggests it's a little less than 16 and fourfold. I think

01:47:42.880 it's sort of maybe closer to tenfold and twofold, but we don't need to worry about that. There's no

01:47:46.920 question it's high risk, but it's important to note it's not deterministic.

01:47:49.500 No, it's not deterministic.

01:47:50.980 And in fact, it's far less penetrant than FH is.

01:47:55.260 Yes, it is.

01:47:55.780 There are lots of people walking around with APOE4 that are not getting Alzheimer's disease. And as you

01:48:01.020 pointed out, a third of people with Alzheimer's disease don't have APOE4. So everything we're

01:48:05.900 talking about here is fair game to everybody. What you said that's interesting that I didn't

01:48:10.240 realize until today was APOE1 can traverse the blood-brain barrier. And therefore, if you have

01:48:20.040 a therapy that raises APOE1, you can potentially offset the damage of a defective APOE in response

01:48:30.380 to APOE4. Do we have a sense for many of the preclinical work that's been done or even the

01:48:35.460 early clinical work that's been done, what the magnitude of that can look like? Where I'm going

01:48:39.660 with this, of course, is how could we begin to quantify the potential benefit of this? Is this

01:48:48.040 something where, as you probably know, Mike Davidson also very involved in the clotho space,

01:48:54.560 right? Also very involved in looking at the observation that those with clotho KLVS variants

01:49:01.240 seem to have almost complete protection from their APOE4 gene. It's a remarkable finding.

01:49:09.320 Yeah. So there is one large Mendelian randomization study in E4 carriers and which gene can protect you?

01:49:19.000 loss of function of CTP. So we already have Mendelian randomization data in humans that low CTP

01:49:27.880 protects an APOE4 carrier against Alzheimer's. But what you just asked me is, can we have an effect

01:49:35.380 size here? We are doing a proof of concept trial where we tap cerebrospinal fluid and we look at,

01:49:43.840 I mean, like 50 biomarkers. Because what we hope is that APOE1 goes up in the brain.

01:49:52.160 That the consequence of that is that the cells are going to normally synthesize cholesterol.

01:49:58.880 So the desmosterol and lactosterol levels should go up because cholesterol synthesis is normalized again.

01:50:07.080 At the same time, 24-hydroxycholesterol should also go up because cells are getting rid of cholesterol

01:50:13.480 in a normal fashion. And the inflammation biomarker should go down because you basically substitute

01:50:21.560 for this dysfunctional E4. So in order to understand the effect size, we need to be able to make a story

01:50:28.620 where we say dysfunctional E4 replaced by A1, normal cholesterol synthesis is on again,

01:50:36.940 normal cholesterol removal is on again, inflammation goes down. And of course,

01:50:41.860 this proof of concept trial is only six months. So there won't be much in Alzheimer biomarkers.

01:50:46.840 But if we can show that we improve lipoprotein metabolism in the brain,

01:50:50.940 it is a first step into a fascinating journey, I would say.

01:50:55.500 Will you be measuring desmosterol and lactosterol in any of these trials or in all of them?

01:51:00.540 Yes. Yes. No, we, in the Alzheimer trial, we do.

01:51:03.940 Which is prevail is the one where you're going to...

01:51:06.100 No, no. The Alzheimer trial has no name. The Alzheimer trial is a trial in...

01:51:11.080 Oh, it's a fourth trial. It's a fourth trial. It's a fourth trial. Yes, it's a fourth trial.

01:51:15.480 But we have no name for it because it's in a single center in Amsterdam and it's a large Alzheimer

01:51:21.320 center where we have basically mild cognitive impairment with a diagnosis of Alzheimer. So

01:51:28.780 early Alzheimer, we give them our drug and we serially measure both blood and CSF by spinal taps.

01:51:35.800 I got it. But you will not be in prevail, for example. Will you be looking at lithosterol,

01:51:41.140 desmosterol levels? We have a lot of spare tubes. So that is definitely something that,

01:51:48.320 you know, we have a quite a wish list of things where we want to look at. Yeah.

01:51:52.880 Well, inquiring knuckleheads like me want to know. Let's close out our discussion,

01:51:57.940 John, with an explanation of the role of APOE in cardiovascular disease. Because it,

01:52:05.040 you know, APOE gets a lot of attention for what it's doing in the brain. We just had a pretty

01:52:09.940 brief but insightful discussion on that. But I think people are less clear on the relationship

01:52:16.180 of APOE in the heart. So what can we say about atherosclerosis and APOE?

01:52:21.080 Again, APOE4 might have been wonderful during the ice age, but now it's bad because it's associated

01:52:29.180 with higher LDL. It's associated with a more pro-inflammatory state and it's associated with

01:52:36.060 more heart disease. Now, if people have a hard time believing how it's possible that when you're

01:52:42.820 in E4 that you have higher LDL, the explanation is, is that APOE, of course, sits on VLDL and on VLDL

01:52:51.260 remnants. And APOE4 actually is a better ligand for the LDL receptor. It's an amazing story,

01:52:57.920 the APOE story. Better ligand than E3E2. And so, especially the chylomicron remnants and the VLDL,

01:53:04.680 so IDL races into your liver and that will downregulate the LDL receptor and therefore

01:53:11.440 LDL goes up. Sorry, just to make sure folks understand that because that's, it's a bit

01:53:15.840 counterintuitive, right? This is a little bit of a paradox. It is totally counterintuitive.

01:53:20.260 If you have APOE4 and it's a higher affinity ligand for the LDL receptor, it should mean that

01:53:29.900 APOE4 generated proteins lead to more rapid clearance of LDL. But if I understand you correctly-

01:53:38.000 Not LDL. There's no APOE on LDL. Yes. Yeah. Okay. Sorry. Sorry. Yeah. So-

01:53:44.520 Because it's all on the remnants and on VLDL. I see. And that's the point. So because it's

01:53:49.060 the remnants and the VLDL, those readily get attracted, downregulate the LDL receptor. So

01:53:55.660 there's less LDL receptor to get rid of LDL. Is that the chain of events?

01:54:00.780 That's the chain of events. But there's much more to E4 than just a little lipoprotein metabolism.

01:54:07.220 There's, like in the brain, there is enough association with other things that you don't want. I mean,

01:54:13.920 this chronic pro-inflammatory state that people like Paul Ritker, you know, has made his life's

01:54:20.520 work of is also associated with an E4 carriership. And does the association with APOE4 in terms of

01:54:29.840 risk vanish once you normalize for APOB? Or is there still residual risk based on these other factors,

01:54:38.080 such as inflammation, that exist and persist once you've normalized for APOE3 versus APOE4

01:54:44.680 in the context of the same LDL-C slash APOE3?

01:54:49.220 If you ask Alan Snyderman, he'll say that if you control for APOE3, everything falls away.

01:54:56.600 And that it's the number of, you can also look at NMR, LDL particles, but that APOE3 is really,

01:55:03.660 is really what drives all our statistics in cardiovascular disease. It's very interesting.

01:55:09.240 For example, you've seen the bampidoic acid data. So the clear outcomes trial was on the line

01:55:16.180 of absolute LDL lowering versus MACE reduction. So where is the room or the space for the CRP lowering

01:55:26.540 effect if you're on the line? And I really admire Alan Niemann. He has been stoic in his emphasis

01:55:33.980 on APOB for so long. And finally, he gets this kind of vindication now where most people would

01:55:40.260 agree that non-HDL and APOB are a better prognostic marker and a better measure of therapy than LDL

01:55:47.160 cholesterol by the Friedewald formula. But if you ask me personally, Peter, I think that APOE4 has a few

01:55:54.320 properties that you cannot completely knock out statistically or biologically with APOB lowering.

01:56:02.280 Yeah, I don't think that's a big stretch. And it might be that Alan's view and that view are not

01:56:08.440 completely at odds, right? It could be that those other effects are small enough that on a clinical

01:56:14.860 level, you would need really large sample sizes and lifetime exposure metrics to see the difference.

01:56:21.480 It also could be that there are other amplifying features. In other words, if you take two healthy

01:56:28.620 people, one E4, one E3, with the same APOB, the risk is relatively similar. But if you take two

01:56:37.660 unhealthy people, type 2 diabetes, NAFLD, profound insulin resistance, one E4, one E3 with the same

01:56:45.760 APOB, it could be that those other factors create more of a gap between those people on a Kaplan-Meier

01:56:53.100 curve. I think that that's very reasonable. And I tend in that same direction.

01:56:58.440 I mean, I think for me, part of the takeaway here is just that I'm trying hard not to be excited,

01:57:03.520 right? I think that, as I said before, when you're once bitten, twice shy, and I've been a very vocal

01:57:10.600 critic of these trials, meaning the last 15 years of CTEP inhibitors. And I would say that perhaps I've

01:57:19.820 been too harsh, and I've been mostly a critic of the HDL hypothesis, and I've relied on the CTEP story

01:57:29.440 along with the Mendelian randomization as my rationale for that. And in reality, I think that

01:57:35.420 that has created a little bit of a blind spot in my eye towards a more pure biologic understanding.

01:57:42.080 And of course, I'm the last person who should have this blind spot because part of my interest is in

01:57:47.760 longevity. And it's clear to me that CTEP is a longevity gene, meaning the hypofunctioning variant

01:57:54.200 is as much a longevity gene, if not more, than the hypofunctioning PCSK9. So it's with the tincture

01:58:00.760 of embarrassment that this is sort of my mea culpa to say, I have been too down on CTEP inhibitors,

01:58:06.640 and I'm very hopeful that Obisetribib not only redeems the field, but also gives me something to

01:58:12.520 be excited about clinically in my practice. Thank you very much for that. And to be quite

01:58:17.680 frank, I was much like you for a long time. And it is, you know, you have to imagine the kind of

01:58:23.760 turnaround you have to make in your head. I was a strong believer in the HDL hypothesis

01:58:28.640 until the Roche trial. Then I had to turn around away from HDL, back to LDL and APO-B,

01:58:36.760 and then understand the blood pressure effect, understand the mistakes in the trials, try to

01:58:42.160 find a drug that didn't have all that baggage. My first New England paper was in 1987. What we did

01:58:49.300 is we measured CTEP activity in a coronary angiography trial. In those days, we only had coronary

01:58:56.140 angiography with pravastatin. And it was, if you had high CTEP activity, you had the worst progression

01:59:03.180 of coronary disease over that two-year trial. So that taught me that CTEP was bad. And since that

01:59:09.540 day, I'd wanted to find an inhibitor that was something that I could work with.

01:59:15.260 It's such a beautiful story. You've articulated it very well, John. And I do hope that at some point,

01:59:22.900 you find the time to write kind of a clinical philosophical paper about science, which is,

01:59:29.480 we lost our way, we as the field, meaning I'm just observing the field, but the field lost its way

01:59:37.160 in this drug based on the wrong biomarker. We were using HDLC as a biomarker because we didn't

01:59:46.180 have a better biomarker for CTEP inhibition. And so the initial insight in the biology was right,

01:59:53.180 but by having the wrong biomarker and failing to understand the mechanism of that, 15 years,

02:00:02.280 and I don't know how many billions of dollars, but it's probably approaching 10 billion, if not more

02:00:08.380 dollars were wasted. And tragically, by the way, it should be noted, some lives were lost, right?

02:00:14.060 We don't want to lose sight of the fact that this resulted in lives lost during these clinical trials.

02:00:19.920 And that's the price we do pay as a society to advance knowledge. I don't want to suggest that

02:00:25.200 you can never have a loss of life in a clinical trial, but it's just a sobering story.

02:00:30.840 But if you would forget about everything that happened before, what we want nowadays is strong

02:00:37.420 Mendelian randomization evidence. We want lots of phase one and phase two trials to show that there

02:00:43.680 are no some bizarre side effects. And then you gently go into a phase three with a DSMB and

02:00:50.060 everything. And you don't do a phase two where you see a blood pressure effect and you say,

02:00:55.120 oh, what the hell? And you know, that would not be possible today anymore. Fortunately.

02:01:01.000 And that's a good thing. Yeah.

02:01:02.040 Yes.

02:01:02.960 Well, John, I'm really glad that Tom reached out to you to ask if you'd be willing to be on this

02:01:08.440 podcast. I'm grateful that you were able to accommodate my time today. And thank you again for

02:01:13.080 the work you're doing. And I'm very excited to follow this story as will the other listeners

02:01:17.500 today. We'll have data on Alzheimer in the summer. Really thrilled to understand what's happening in

02:01:23.800 the brain. Yeah. Fantastic. Okay. Thank you so much, John. Have a great evening.

02:01:27.280 Have a great weekend, Peter. Thank you for listening to this week's episode of The Drive.

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The Peter Attia Drive - May 22, 2023

#255 ‒ Latest therapeutics in CVD, APOE's role in Alzheimer's disease and CVD, familial hypercholesterolemia, and more ｜ John Kastelein, M.D., Ph.D.

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