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.

Episode Date: May 22, 2023

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter John Kastelein is a renowned expert in lipoprotein metabolism and atherosclerotic cardiovascular disease (ASCVD) research. In this discussion, John delves deep into familial hypercholesterolemia (FH), a genetic disorder characterized by high levels of LDL cholesterol in the blood that increases the risk of developing heart disease. He covers its definition, genetic underpinnings, and clinical identification. He then explores the therapeutic options available for the prevention and treatment of cardiovascular disease, including the captivating history of CETP inhibitors. He explains the past shortcomings of previous CETP inhibitors before underscoring the compelling potential of the latest iterations, not only for cardiovascular disease but also for conditions like Alzheimer's disease and type 2 diabetes. Moreover, he unveils the intricate role of APOE, shedding light on why the APOE4 isoform codes for a protein that significantly increases the risk of Alzheimer's disease and cardiovascular disease. Concluding the discussion, John shares a profound sense of optimism, envisioning the possibility of targeted therapeutic interventions for high-risk patients in the near future. We discuss: Familial hypercholesterolemia (FH): a genetic condition [4:30]; Differentiating between phenotype and genotype when it comes to FH [9:45]; The pathophysiology related to mutations of FH [15:30]; Clinical presentations, physical manifestations, and diagnosis of FH [22:00]; Why a small fraction of people with FH do not develop premature ASCVD [34:15]; Treatment and prevention for those with FH [39:45]; Addressing the assertion by some that elevated LDL is not casual in cardiovascular disease [52:45]; The history of CETP inhibitors, and the role of the CETP protein [55:45]; The thrifty gene hypothesis and why genes underlying FH may have been preserved [1:09:00]; The compelling potential of the latest CETP inhibitor (obicetrapib) [1:13:00]; Promising results from phase 3 trials exploring obicetrapib [1:27:45]; Why the APOE4 allele increases the risk of Alzheimer’s disease, and the connection to blood lipids [1:41:30]; The role of APOE in cardiovascular disease [1:51:45]; Takeaways and looking ahead [1:57:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of the space to the next level. At the end of this episode, I'll explain

what those benefits are, or if you want to learn more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. I guess this week is John Casteling. John is a genetic researcher and clinician scientist known for his work in the field of familial hypercholestralemia and the development of lipid modulating drugs. He is currently a professor of genetic medicine at the University of Amsterdam, where he leads the department of vascular medicine. John has been the main driving force

behind the development of a treatment for homozygous familial hypercholestralemia, a severe form of FH. Now, some of you may be listening to this saying, what the heck are you talking about? Well, it's important to understand that FH or familial hypercholestralemia is the second most common form of hereditary heart disease, right after elevated Lp.lA. And you know from probably listening to previous versions of this podcast,

that elevated Lp.lA is staggeringly prevalent in the population, and by extension therefore, so too is various forms of FH. And while we use FH as an important place to start this discussion because it becomes an important way to understand therapeutic options, the subject matter that we cover here is of course applicable to anybody who's interested in minimizing the risk of cardiovascular disease. John has also led several clinical trials, including the pivotal Odyssey, Long Term, and Odyssey outcomes studies which helped to establish the safety and efficacy of PCSK9 inhibitors in the treatment of FH and other forms of hypercholestralemia. As I said, we start the discussion by focusing on familial hypercholestralemia.

We talk about what it is, how you define it, how you can be aware if you have this, what the genetics are, that underpin it, what we do with kids that have this, etc. We then talk about the history of C-Tep inhibitors, which is indeed a sorted history. These have been a class of completely unsuccessful drugs that have resulted in much hype and fanfare without any tangible results. However, John makes a pretty compelling case for the most recent version of these drugs to be not only a potential game changer, a word that I hate for cardiovascular disease, but perhaps even more interestingly for Alzheimer's disease and type 2 diabetes.

This dovetails very nicely into our final topic of discussion, which is that in the role of APOE. Now, traditionally, when you hear me talk about APOE, I'm talking about the gene APOE, and it's three isoforms, APOE2, APOE3, APOE4. It's important to understand that, of course, those genes code for a protein that goes by the same name, APOE, although it is not fully capitalized, and that's how when you're reading it, you know the difference. What we talk about in this episode is what that actual protein does. And why is it that someone with the apoe4 gene codes for a version of that protein, which by the way, only differs in one amino acid from the one coded for by apoe3, and we talk about

why the protein that is coded by the apoe4 isoform produces a much greater increase in the risk of Alzheimer's disease and cardiovascular disease. What's most interesting to me about all of this is that it ties back very nicely to the discussion of how this most recent C-TEP inhibitor might work. And what I'm left with is a sense of profound optimism that sometime in the next five years, we may indeed have therapeutic molecules that we can use specifically for high risk patients, such as those with APOE4. So overall, I would say this discussion surprised and delighted me much more than I expected. And I know that even though it's a technical topic, it is something that is going to be of great interest to anybody who cares about heart health and brain health.

So without further delay, please enjoy my conversation with John Castley. John, thank you so much for staying up late into your evening in Amsterdam to make time to speak with me. This is a podcast that really came across my radar courtesy of one of my mentors, Tom Despring, who basically got me interested in the work you were doing and said, look, if you'd like to speak with John, we might be able to twist his arm to make time for this. And so I'm both gracious that Tom got me into your work and that he was able to convince you to sit down with us. So, am I? As you know, because you mentioned to me earlier that you've listened to the podcast,

you're probably familiar with how much we talk about cardiovascular disease. It's not really an accident, right? I mean, it is the leading cause of death globally. I don't think you can state the stats enough, right? I mean, the last time I looked, 19 million people died in the world due to ASCVD, and the second place killer was cancer at something like 12 to 13 million. So it's not even close that what we're talking about is the leading cause of death. And it's for that reason, I think that we need to make sure that we take every opportunity to educate people about this. And I want to start with a genetic condition called familial hypercholestralemia, which

is probably far more prevalent than people realize. In other words, there are thousands of people listening to this podcast who are affected by that. So tell us what FH as it is abbreviated is. Yeah, so we were the first in Holland who actually had a very large-scale organization to find these people. So I trained in Vancouver. I was a visiting professor also in Vancouver by Michael Hayden. I had my Canadian exam, so I did lipid clinic in Vancouver in a time when there were no lipid clinics in Europe or hardly.

So when I got back in Europe and I started the lipid clinic in Amsterdam, about 60% of all my referrals were FH. And I thought, why would that be? And then when you go back into the history of my country, my country is about the size of Rhode Island. And it has 18 million people. These people have not really moved in the past. So there are large provinces with consanguinity. It's not consanguinity, as for example, with the French Canadians or the South Africans, but it's nevertheless consanguinity. or the South Africans, but it's nevertheless, kronsangrinity.

So we got a huge 30 million euro grant from the Dutch government to actually start actively find these people. Because when I started doing this in our large Libertal Nikon Amsterdam, we still had mortality or severe anterior MIs at ages between 20 and 30 in men, for example. Wow.

So I can almost remember all of them, people that were fit like you, period M.I.s at ages between 20 and 30 in men, for example. Wow. So I can almost remember all of them, people that were fit like you, but didn't know they had an LDL of 300 mixed predestinator from their birth onwards. And actually we're playing some tennis and then they got a massive anterior M.I. And in those days there was not much stenting yet. And so the only thing you could do is put someone in a cardiac care unit and actually do all kind of vague superficial things. So FH is a true autosomal dominant disease, meaning it's not sex linked, you don't need two parents to get it, you only need one parent to get it, it's almost a hundred percent penetrant, meaning that if you have a robust mutation in one

of the genes that cause FH, you're almost certain to get the phenotype. And the phenotype starts very early. We have in Amsterdam the largest pediatric lipid clinic in the world. We have seen over 2,000 children with heterozygous FH. So we know that this disease starts very early in life, then becomes symptomatic in your teenage years, in the sense that the cholesterol that is elevated in the circulation starts depositing on your tendons, especially the extended tendons on the dorsum of your hand and in your Achilles tendon. And then also you start very slowly seeing the Arches,

so the Arches in the eye and sometimes the deposits on your eyelids, the Chantalosmeta. And so those are the physical manifestations of the disease and then very often especially in the old days, the first really serious manifestation is either an angina or a heart attack. And one of the things that is so dangerous about this disorder is that it's the plaque that you get in FH is a soft plaque. It's a cholesterol-rich, large plaque that is very often proximal in the coronary arteries, meaning that if a plaque like that bursts, you either have an occlusion of your entire LED or you have a mainstam occlusion,

which kills you right on the spot. You know, sudden death actually. Those sort of proximal left main or distal left main are what's referred to as the Widowmaker. I want to just back up and make sure some of the stuff that you said makes sense to people. So you said so much there that has my eyes wide open and I understand this stuff. So I just want to make sure everybody gets it. So a couple of things.

Let's differentiate when you use the word phenotype and genotype, let's explain to people how one defines the phenotype of FH. In other words, what is the objective metric by which we define this condition? So the objective metric, as with all patients, is history first. And very often in these families, there is a family history of premature coronary disease. That's one of the first things that speaks for these families. Then second, these people have elevated LDL cholesterol without any other abnormality. So, HDL's normal target rights is normal. LDL is elevated. And you need to find

elevated LDL in first degree relatives also. So in children of that individual or in one parent and in siblings. And with that LDL, you can reasonably construct a family tree where you know who's affected and who's not. But unfortunately, as you undoubtedly know, there's overlap between affect family members and affect the family members in alkyl stroll. That's why we decided a long time ago to go for the mutation, so to go for the genotype. Because of course, for the genotype, there is no overlap. Either you carry the mutation or you don't carry the mutation. Now, this is where we have a bit of an issue, right, John? Because unlike, don't carry the mutation. Now, this is where we have a bit of an issue, right, John?

Because unlike, for example, LpLittleA, which we've had several podcasts on where the phenotype is unambiguous. You have an elevated level of LpLittleA, the lipoprotein. The genotype is also very clear. It's a one-to-one mapping, right? Lpa is the gene that codes for apolipoprotein LittleA and away we go. Here, we have a very heterogeneous

genetic set of causes. In fact, I could be wrong on this, so please correct me. I believe I've read that there may be over 3500 different mutations that would roll up into FH i.e. that would roll up into FHIE that would produce this phenotype of, and are we using, by the way, an LDLC cut off of 190 milligrams per desoleter? Yes, that's what we are mostly using, 190. Of course, if you start a lipid clinic and you get referrals, there's a referral bias, so the initial patients that I saw all had LDLs of 300 or more. Now, the genotype is very interesting. So what we've done is, of course,

if you start determining a genotype, you have to be absolutely sure that your diagnosis is correct because if your diagnosis is not correct and you don't find a mutation, it's meaningless. So what we've done is we've used the children as our kind of diagnostic linchpin, because if a child has high cholesterol, with the exception of primary hypothyroidism, there's almost no other course for elevated LDL

cholesterol in a child. Then FH. Right. And it's important to explain, I think, the people that, although you've alluded to it, I want to make sure people understand. There are a lot of people walking around with an LDL cholesterol of 200 milligrams per desolator. Oh, yeah. But they might have triglycerides of 300 milligrams per desolator, they might have type two diabetes, they might have thyroid disease that is untreated,

they might have renal disease that is untreated, there are lots of other diseases for which a side effect is elevated LDL cholesterol. And what you're saying is, look, we got to rule those out, right? Yes. And therefore, we started in the children, Peter. That's my point.

Yes. Because in the kids, there's far less likely to see those other diseases. Yeah, it's almost in all the thousands of kids we've seen were just a handful had had the secondary course for elevated LDL. The vast majority actually all had a genetic course. And we've published this in JAMA and in Lancet. So when we we had a cohort of 220 children where we had three generation family of elevated LDBL. So there was no doubt that they had FH. Then we started sequencing. We could find a mutation.

I mean, next generation sequencing, everything, exonentrum, the whole in 95% of cases. So that is a very different number than what you normally read in the literature for adults, where people can find 50, 60% at the max and they have no explanation for the other 40%. Telling you that the diagnosis, the clinical diagnosis, is not that good yet in adults, unfortunately. But it's very good in children, 95% mutation. So out of those 220 kids, 5%

which is 11 kids, we also have never ever found a mutation. And we've really tried. So that tells me that there are more genes. There are mutations we don't know about yet. Exactly. Now, the 95% if you make that a hundred percent Then it's 95% TL the L receptor four and a half percent Epob and point five percent BCS K9 gain a function mutations So that in a country like ours

Is the division between the different genes? L the receptor vast majority. And here it's not that profound, right? I mean, here in the US, I was always in an impression, it's probably called 70, 80% is LDL receptor. It's probably more like that in the US. Yes. And let's explain to people what's going on here.

Again, I think it's worth understanding the pathophysiology because we'll get into treatment. But when we say mutation in LDL receptor or mutation in APOB or gain a function in PCSK9 protein, explain briefly what each of those means and why would each of those translate to the higher biomarker that people are used to seeing. Everybody listening to this knows what their LDL cholesterol is, but why would these mutations lead to 3x normal levels of LDL cholesterol? That's actually a wonderful and very easy to understand story. So every LDL particle has an APOB protein kind of cringled around it, almost like a snake. And one area of that protein is sticking

out of the LDL sphere. And that is a binding domain. That is around amino acid, 3,500. We actually know that. Then there is a receptor for that particle sticking out from your liver cell, your hepatocytes. And these two bind normally. So the LDR receptor grabs the LDL particle and then the whole complex is internalized into the lysosome and the zone where it's basically dealt with. Now next to the LDR receptor on the hepatocytes surface sits another protein called PCS-K9. And that protein degrades the LDR receptor. And that is the balance in nature.

Because you can't have at least not in the old days in evolution. You can't have an overactive LDR receptor because then you clear every LDR particle for musicallylation. So you have to have a balance. And the PCS-K9 protein that the great STLDL receptor gives that balance. But if there is a mutant in the binding domain of EPOB, you have something that we call FH or familial defective EPOB, which is basically the same. If you have a mutation in the LDL receptor, you can't bind the FOB. And then if you have a very active PCS-K9 and you basically degrade all your LDL receptors, the end result is the same. There's not enough LDL receptors for the LDL particles. So all three things converge at the surface of your liver cell and a problem with either one

of the three always leads to elevated LDL cholesterol. And that leads to all the downstream things that we just discussed. So for folks who like to anthropomorphize things, you can picture the LDL with the APOB wrapped around it as a baseball. The LDL receptor is a baseball mitt sticking out from the liver and the PCSK9 protein is something that smacks the mitt and closes it. And so basically one form of mutation is mutations that change the shape of the baseball mitt. So it can't catch the ball or it catches it very poorly. Another mutation changes the shape of the ball. So the ball

doesn't fit in an otherwise perfect baseball mitt. And then the final mutation is one that makes too many of the things that swat the baseball mitts. Absolutely. But if you make the diagnosis right in a child with elevated LDL cholesterol, you've excluded the rest. You know, his father has a high cholesterol, his grandpa had a high cholesterol. One sibling has a high cholesterol, you know, yeah, well, this is FH. Then you do a mutation screen, you find in 95% of cases, you can find a mutation, the vast majority is the LDL receptor, then comes Epi and then comes PCS, can I so in our country, PCS can nine mutations gain a function are very rare, 4.5%.

You know, another mutation that we've seen even in our practice and we have a very small mutations gain a function are very rare, 4.5%. You know, another mutation that we've seen even in our practice, and we have a very small practice, but I suspect we also disproportionately collect people who are higher risk, but I've seen two cases of what appears to be ATP binding cassette G5, G8 loss of function. So we see people who have FH and I mean, I can't rule out LDL receptor defects or gain a function PCS K9 because we're not going to do that genetic test.

But what we can see is that they have levels of cytoastural and compester all that are more than a log fulled higher than the 95th percentile. And from that, I don't know, would you agree that we're imputing? It does change our management, because as Adam, I becomes first line, but more importantly, just as a very curious finding, would you agree with our likely inference that that's probably the driving mutation in those people. I would completely agree and I'll take one little step back. So mutations in these three genes that we just described are very prevalent in the general population. In fact, we have calculated that they are probably like one in 250, which makes FH by far the most frequent autosomal dominant disorder in men. Now the Koreans and a number of other people have actually looked in children with high cholesterol at cytosterol and cholesterol levels.

As you know they should be like 12 for cytosterol and 14 for cholesterol., if you put the level at like 35, they find a proponderance of kids who have increased plant steriles in their circulation, and they find mutations in ABCG-5G-8. So, in the old days, we thought that cytosterolemia, which is the disorder associated with ABCG5G8 was like one in a million. That is probably a huge underestimation. And based on a number of studies in different countries, we now think it might actually be like one in 150,000 or so. 10 times more frequent than we originally thought. And what we also didn't appreciate is that if you are heterozygous for a loss of function mutation in ABG 5G8, you also have exactly, as you said, increased cytoosterol and cholesterol levels. And so very likely these disorders, especially in an advanced clinic like yours, will

go inside quite frequently because they are not rare. They are actually both not that rare. So I have exactly the same experience. Let's go back a little bit to this clinical presentation. We talked about it, but I think some of these physical signs might be surprising to people that go beyond the obvious, which is sclerosis. So you mentioned tendon, zanthomas, you mentioned cholesterol deposits elsewhere in the body, explain a little bit more about if we understand why does cholesterol tend to accumulate in those particular areas, for example, extensor tendons over flexor tendons. Do we have a sense of why that's the case? The theory is that it's linked to movement, Peter, so that tendons that are used very, very frequently,

that there is around those tendons, there is a preponderance of macrophages and monocytes. These monocytes, macrophages, are capable of storing LDL cholesterol. And when there are enough of them, you actually see it. You physically see it and you can feel it also. So the two most frequent places where you'll find these deposits are the extensor tendon of your hands, which you use the whole day. And of course, you're a killist tendon, but in my career, which, as you can see on my gray hair, has been a while, I've seen Xen Xantoma too, also in the Patelah, and so that tendon, actually on the tibia.

I've seen them under wedding rings. So actually Xantoma under a wedding ring. I've seen them everywhere. And then the deposits on the eyes are probably also linked to movement because you're blinking your eye the entire day. And then you have the positive cholesterol in your cornea, which is called an arcus cornealis. So it's not in your lens, it's in your cornea. Why that is, there is a lot of conjecture about it, but I don't think people really know. But sometimes actually I have made the diagnosis

of FH once in a KLM airplane. So I was kind of lying. There was a stewardess who wanted to give me a drink, and she had very blue eyes, you know, these Dutch blue eyes, and I looked in her eye, and I saw a ring. I said, when you go back, you need to have your cholesterol checked and she proved to have FH. So sometimes you can make the diagnosis by really paying attention in the subway or etc. Because also the extended tendons on your hands are sometimes really visible. There are a number of old Dutch paintings from the 17th century where you can still see the tendons and tomas on the hands.

Wow. And of course they obviously had no idea what was causing that shape, but it was, they wanted to be as accurate as possible and they painted it. So we've established how the diagnosis is made. Do you require the clinical manifestations for the diagnosis. In other words, if you have a 50 year old person who has had elevated LDLC for as long as they've had blood tests, so they would say to you, yep, you know, doctor, going back into my teens or 20s, I had LDLC north of 200 milligrams per desolate,

my doctor's always said, that's too high, and I didn't care, blah, blah, blah. But now that he's standing in front of you, and you examine him, and he has no evidence of Xanthomas. No Arcus, nothing at all. No physical sign whatsoever. You send him for a CT angiogram and his coronary arteries are clean,

but lo and behold, his father also has elevated cholesterol. Let's say he died of heart disease at the age of 78, so he died, but not prematurely. Absent a genetic test, which I assume would seal the deal. Do you say at least phenotypically, he still meets criteria for FH? And also, let's assume that you've ruled out every other medical thing. So he doesn't have hypothyroidism or kidney disease or insulin resistance. You don't need the physical stigma to make the diagnosis because we've seen that time

and time again. There are people for some reason that have very elevated LDL cholesterol. It is genetic. It is dominant. It is, but it doesn't lead to the physical stigma. What I haven't seen that many times is what you're describing is that the CT&JO is normal in a 50-year-old. So if someone tells me that they had in their teens or late teens or when they went into the military, you know, when they're 18, they had an elevated LDL cholesterol and when you then see them when they're 50 and they haven't been treated to have a normal calcium scoring and or a normal CT angel, that is really rare for LDLs, let's say, you know, between two and three hundred. That's really rare. But we've seen them and it's interesting is that so there is a cholesterol overlap. It's like a Gaussian distribution for people like you and me. Then there's also a Gaussian

distribution for heterozygous FH. There is an overlap between the two, but now we know, and Evan Stein and I have actually published about that, is that there's also an overlap between homozygous FH and the end of the distribution of heterozygous effage. So you can never use LDL alone as a hundred percent certain marker for your normal UF heterozygous effage or UF homozygous effage. This is a syndrome diagnosis. So you need family members, history, and arcus, and this and that. And then what's also very important is what you said in the beginning, that this is a unique LDL disease. The moment there's elevated trigysurides, for example, and low HDL, then you immediately have to think about something entirely different, especially in a individual that's not obese or diabetic.

Let's go back and make sure we explain to people the difference between what I assume is much more common, which is heterogeneous FH and homogeneous FH. Can you explain to people the difference between what I assume is much more common, which is heterogeneous FH and homogeneous FH. Can you explain to folks what that is? The terminology I find sometimes difficult. So we know, and I'm sure you've discussed that also, I think with Dan Raider, is that there's called polygenic hypercholestolemia. That sometimes is so severe, the polygenic hypercholestolemia, that it looks a lot like heterozygousophage. And some people even say, if you've had those genes also from birth onwards and you've had a high LDL cholesterol,

you know, from a young age, the risk of that severe polygenic hypercholestolemia is just the same as for heterozygousophage. I still find that difficult because I see when you go look at premature mi for example, patients with premature mi, there's a huge enrichment for real heterozygous fh. So the homogenous heterozygous fh, the heterogenius fh or polygenic hypercloslemia, whatever you want to call it, is in my view still a less severe clinical picture. I've never seen people with that side of the spectrum get heart attacks in their 20s or 30s. So we have found 25,000 hepatosigus of age patients. We've published on this. So it's humongous database. And the monogenic, especially LDL receptor gene mutations, and especially if they're severe,

so a premature stopcode on, so you don't have any protein at all, that is the most severe form of inherited hypercholestolia in my dictionary and in my experience. But truth is, is that your polygenic or heterogeneous FH is probably much more common, even more common than heterosigis, the monogenic form of heterosigis FH. I wanna come back to this distinction when we start to talk about therapy in as much as it changes

either the initial steps we take or the expected number of steps we take therapeutically, but before we do, I want to put a bow on a few other things. Can you formally state again the Dutch lipid clinic criteria and then let me know if that sort of differs from others because I want to make sure that because there are different criteria for this correct and I think one could argue maybe you're biased, but I might share your bias that the Dutch criteria might be the most rigorous. Is that there's Simon broom criteria, there is the WHO criteria and the Dutch lipid clinic. Now the Dutch lipid clinic criteria were put together

by one of my co-workers, Peter Landsberg. And this set of criteria was externally and internally validated with mutations and huge numbers. And every time you do a comparison between the Dutch and the rest, the Dutch are winning in terms of their power to predict a ph. So it's not unlike max for stab in winning the most races, also being dutch, right? Just to clarify that. I don't know how much of a fan you are. I think Max for step one is actually totally brilliant guy and a fantastic athlete. This is just something that you get points.

So if you have a first degree relative with known premature coronary disease, you have a score of one. Or if you have a first degree relative with high LDL, you get one. Then if you have children or you have these xantometer, you get two. I know this is an audio, but it's a long list. And what's interesting is that if you have a mutation, you actually get eight and a diagnosis of definite fh is above eight. So you have definite fh, probable fh, possible fh, and unlikely fh, which is great because you can divide your patient population into these categories. And as you're saying, it has a therapeutic consequence.

Because if someone has definite F age, we treat from the age of six. That's in our national guidelines. And then we start treating immediately just to give you a feel for that. Let's just make sure people understand what was just said there, right? If we can through this very rigorous diagnostic criteria that just for the record was not developed by Max Verstappen, if we can establish that a person has FH with such a high degree of certainty that we would call it definite, we would be treating an individual as young as six years of age, which means our certainty

with which this person's life is at risk in as early as the third decade of their life, i.e. in their 20s. We're so sure of that that we would do something that, honestly, I think a lot of people who don't, especially if you don't really understand the path of physiology of lipid metabolism, would think that's absolutely insane. Now, I obviously share your view, which is that's absolutely not insane. That's the only way that person's going to go on to live a long life. But I would imagine that that's a very difficult discussion to have with the parents. Well, sometimes. Yeah, yeah, I was just about to say, it would depend on what they've already experienced. Absolutely. It's all basically determined by family history. I have seen in the pediatric lipid clinic, especially in the first five to ten years, mothers

with no father anymore. So mothers in their 30s, their husband was deceased. She came with three children and then one child had a total cholesterol of 10, which is like 400 or something. The middle child had normal cholesterol and the youngest child had a cholesterol of 300 or something and so that mother Really wants her child treated. Yeah, she knows that two of her three children inherited the genes that killed her husband at 30. Exactly. Totally unannounced. The first heart attack was the last terrible.

One more question actually, John, before we get to treatment. What is your best guess as to two things? One, the fraction of people with FH who do not go on to develop premature ASCVD. So we'll call this the fraction of people with FH that seem immune to the phenotype. And then of course, the more interesting question is what would be some plausible explanations you would offer for that? So let's start with the easier question if you even, if it's knowable.

We estimate based on our long-term follow-up of that large-dutch cohort that about 5% of people escape any disease symptoms at all. So that includes coronary artery calcium scoring, CTN-Jose, Zental asthma, Zentomus, Arcus, anything. They seem completely immune to the elevated LDL cholesterol. Now, I have to say that the vast majority of those are women. So that's the first thing. In men, it is extremely rare to have that. So the majority are women and very often we discover those women when we go into the family. A child is referred to total cholesterol, 380. There's no thyroid problem, no renal problem, then we go to the father and the mother and the

uncles, and then we find an aunt who's 76 has never been treated and we measure cholesterol and she also has an LDL of 250. And then we do mutations because in Holland, the mutation screening is free. The government pays for that. So we do mutations in everyone that comes to our clinic, basically free. And so then we find the mutation in her too. And there are some explanations. Very frequently those women have very high HDL cholesterol.

So perhaps some people have such an efficient reverse cholesterol transport system that they can take care of the deposited LDL in the macrophage on the tendons everywhere. It's almost like the reverse cholesterol transport back to delivery so fast that you can dump anything on them doesn't matter. So in other words, they have something protective. Yes. They absolutely have something protective.

And so they are almost never smokers. So if you're a man and you smoke and you have FH, it's a death sentence. If you're not treated in the old days or people that are not discovered right now, then really that interaction between one pack or two packs a day with LDL is the worst in terms of heart disease risk. So the women are very rarely smoking. They also almost never have diabetes. So they are thin, active women have high HDLs and don't smoke.

But we have desperately tried, we even had grants and everything to understand genetically if something maybe with these people, we and no one, I think, on the planet has ever found a real good biological reason as to why some people are so resistant against LDL cholesterol. And I assume the sample size is not that large, but has anybody looked at monosigotic twins, both with FH to see if there are differences in progression as a function of various lifestyle factors that might give us a sense of how much of that is driven by divergence in behavior. It's very interesting, by the way, there is one of the largest

monosigotic twin cohorts is in Amsterdam at the other university. Dorad Bomsma, a wonderful researcher, but FH is just too rare to have enough of those monosagiotic twins to make any conclusion. By the way, I just add something based on the discussion with Dan Raider that she referenced that is, the HDL cholesterol story is a pretty complicated story. It's a far more complicated story than the LDL cholesterol story.

The LDL cholesterol story is actually relatively straightforward. We don't know when we measure an elevated HDL cholesterol if it is a biomarker of something good that is happening, i.e. HDL's delipidating foam cells, macrophages, things like that, or if it's a bad thing, I went really down the rabbit hole three years ago on the literature of people with elevated HDL cholesterol who were developing premature

ASCVD. So, the positive that these people with elevated HDLC, that was actually a biomarker for very dysfunctional HDLs. Yeah, those are people with SRB1 mutations. Exactly. We found one family and published that in a wing that's very interesting. These people are very high HDL, but they had premature coronary disease. But remember, the woman I'm describing is a nice, thin, elderly grandmother who's very active, jumping up and down, doesn't smoke smoke and her high HDL is definitely not a sign of something dysfunctional. My point being is this is such a complicated or lack of a more productive word. It's a multifaceted problem for which there might just be in these five percent of people

again, mostly healthy women who seem immune to the phenotype, there's an alignment of the stars where enough other things are working in their favor that it's offsetting this damage. So let's now talk about treatment. And I wanna talk about it through the lens of, are there any differences in how we treat people by sex, by age and by level of disease at time of diagnosis.

So whether we're dealing with primary prevention, and that's a term, I don't know if you would agree with me on this, but I describe primary prevention as treatment when there is not a single discernible sign of disease. Whereas I would call secondary prevention, if you have a calcium score of five, we're already in secondary prevention, even though you haven't had an event. Or if there are abnormalities on the CTA, of course. That's right.

No, I completely agree with you. Primary prevention is rare. That's exactly right. So secondary prevention is, yeah, your CTA might be zero calcium score, but there's a soft plaque well inside the artery. Zero luminal obstruction doesn't matter. You have AACVD that can be documented by the naked eye effectively, not even microscopically, so we're in the secondary providence. So maybe

walk us through primary versus secondary prevention, men versus women, children versus adults, and take that in any order that you like, as far as how you think about treatment. Let's start with the child. So the child comes to us at the age of six years, is the first time a child understands what they eat. And in hetozygous FH, it's very important to start with a very healthy lifestyle early on. So we give them extensive anti-smoking training and we give them extensive dietary counseling

for all the good healthy choices and also tell them sports, physical exercise, so there's a large... Okay, but that never detracts from the fact that we will start with a statin at the age of six. Before you get to that, can you give some insight or color around what type of dietary advice are you recommending saturated fat restriction? Because obviously saturated fats, I think in FH, you probably have a greater likelihood of exacerbating the condition.

Is it true that people with FH are more sensitive, the dietary saturated fat? Or does it just seem that way anecdotally to me? Yeah, that's, I think anecdotally. The problem is, is that we all know that these lifestyle measures are not going to cure FH. They are just supportive, which is very different than for the general population, of course. But hetozygousophage is driven by the LDL and how long a patient is exposed to that LDL. So the earlier we can intervene the better, but actually it's pretty clear that if you start intervening early in LDL, you probably add 15 to 20 years to that life versus doing nothing on the medication from.

So you need to start treating the child. And of course, you start with a statin. Do you have a preference for statin? We used to have a preference for preface statin, because it was kind of seen as the mildest, and we were only allowed in the beginning to use preface statin, because we had done a two-year trial where we showed that corroded IMT in these children in a randomized trial of prevestatin versus placebo, there was

a generation of progression. So we showed already in kids between eight and 18 years of age that was a Yamah paper, actually that we could stop the progression of etero when we treated them with preva statin. And this was way back. And now there are guidelines for the American College of Pediatrics. There are European guidelines. And in some countries they start at the age of eight, other countries are six, but it's somewhere between six and eight. And then you have statin. And I don't think there's much of a preference anymore for a certain statin. Actually, some think there's much of a preference anymore for a certain statin

Actually, some people have a preference for rose over statin because you can dose it at 2.5 milligrams to start with Which is a tiny pill for a kid and then you add a cinema Because you don't go to goals like you do in adults But you try at least to have an LDL below 130 So 130 is kind of the num, I mean, there's no, it's very interesting because there's no intervention evidence for this at all, like in adults. You must have seen the Fourier Olay results that came just out two weeks ago where even LDLs below 20 are better than below 55 are better than below 70. We don't have those data for kids. So. But I was going to say I was actually kind of surprised to hear that you would have such a modest

goal of 130 given that kids without FH have LDL cholesterol levels of 20 and 30. In other words, we know that's fighting conservatism. Yes, yes, yes, no, I don't agree. I personally don't agree with the 130 like probably you don't agree because you and I know what the healthy LDL is for your for your endothelium and is much lower than 130. So, but this is always a fight, you know, where there are there are people that say, yeah, maybe we've done a lot of research. We've looked at growth, say, maybe we've done a lot of research. We've looked at growth, mental state, at learning ability. We've looked at maturation, hormones, monarchy, puberty development, and we've never found any negative effect in kids of statins, but there are conservative people. And so we have more modest goals. But I think it's very diverse. There are pediatricians who treat

kids more aggressively. I guess my point is it's so ironic because we have the natural experiment right in front of us, which is kids are born with an LDL cholesterol 10 milligrams per desolate and as they go through puberty, it starts to go up, but during the most important periods of development, i.e. when their brain is developing, that's doing so in an environment where cholesterol is virtually undetectable. Absolutely. The first year your brain grows by far the fastest, and you have basically no LDL left to go anywhere. So it's completely scientifically agree with you. And by the way, John, has the thinking changed

with PCSK9 inhibitors because I guess you could make the argument, well, statins are impairing cholesterol synthesis and maybe in a developing child, that could be problematic. But a PCSK9 inhibitor has no bearing on cholesterol synthesis. It's simply amplifying LDL clearance. So does that change the thinking at all? Well, it changed my thinking, and I agree with you, but there are other indications,

all preclinical, so pretty useless, in my opinion, that in the embryonic stage, PCS-K9 has a role in brain development, and there are some Mendelian Venomization studies that pick up an increased signal for Alzheimer's disease with low PCS-K9, while all the trials actually have never shown any effect on cognition, but of course those arguments are again used by people that are more conservative. Listen, we have done all the trials because we have so many kids with heterozygous fh for the files of both alerochemap, avalochemap, we've done all the trials in children for heterozygous fh. Also for symphastatin plus zidemib, all the statins alone we've done praophage. Also for symphostatin plus a zidimib, all the statins

alone we've done prava, we've done rosuva statin, we've done symphostatin and then symphosatin and a zidimib and then the pieces can I monoclonals? And so we've done all that and the kits are, it's so interesting, kits are not statin intolerant. Meaning you don't see kids developing my alges and statin-related muscle symptoms. No. Because in adults, we see that about 5% of the time. You're saying you don't see that in kids? No.

Because they don't write the inserts. They don't read the inserts, yeah, exactly. Sorry, they don't read the inserts. But do you think it's also because you're disproportionately using preva statin, which is milder, or do you think it's true even in the presence of razzuvastatin? No, it's also true in the presence of aitorbastatin and razzuvastatin. Yeah. And listen, it's very interesting because we have now a follow-up, and I think that was

a new ink and paper. We have, of course, the kids that were eight are now 18, 10 year follow up, and the kids that were 18 are now 28. So we have compared these kids with the generation above them at that age. And none of these kids actually got a heart attack or angine or anything. And the generation above them who didn't get any treatment, of course, because there were no statins or nothing, their early mortality, early coronary disease was rampant.

So I think we've already shown, although it's not a real randomized, controlled clinical trial, but it's the only way you can do this. You can't randomize a kid. Of course, you can only do observational data. Is that treating from an early age actually protects the kits against premature death and premature coronary disease? Okay, so I want to move on to another topic, but before I do, I guess the last thing I want to contrast this with is the adult middle-aged or otherwise, who shows up either with or without disease.

How aggressive do you go there? As aggressive as the guidelines tell us to go for non-FH patients. So the kids are transferred from the pediatric lipoclinic to the adult lipoclinic, when they're 18, and then we immediately start with PCS-Canine monoclonal and pretty soon with Inclisoran and Zidemite, and we really strive for the lowest LDL possible for that individual. And in the homozygote, we do high dose statin, ezydomype, evalochumap, and now epinachumap, the Regeneron, and SpTL3 monoclonal antibody.

So those four things constitute the state of the art therapy for homozygosephage. It gets a lot of patients to relatively normal LDL levels. And that is a miracle for homozygous FH. In heterozygous FH, there are about 10% of patients that even with triple therapy, we can't get them to a reasonable LDL. So we call these now severe heterozygous FH. They probably have more than one mutation. They probably have another mutation somewhere else that makes it a more severe phenotype, but that we officially don't know that. Meaning these patients on PCS-K9 inhibitor plus statin pluses etymide, you can't get below 70

milligrams per desolate or what? Oh, no, we don't get them below 100 or below 120. So some of them are really they've nasty opposition against your therapy. And it's linked by the way to the starting LDL. So we say that if your starting LDL is above 300, you have severe heterozygous effage. And that's about 10% of the overall heterozygous effage and that's about 10% of the overall heterozygous effage population. Of course, when you start at 300 and you have a statin that takes up 45% then another new baseline 15 to 20 and then you can calculate that it's not that easy to get below 100.

Is A for recess even a viable option? Is it easy to get below 100. Is A for recess even a viable option? Is it easy to pull out? I know it reasonably works for LP, little A, but does it work for the majority of the APO B bearing lipo proteins? It does. We have an A for recess center in Amsterdam, because we've sometimes diagnosed homozygous fage after six months in kids of six months that had a very severe homozygous of age. And then we've had to LDLA for these kids. But I can tell you one thing, every knock him up is the golden rescue for these children.

It's still only used in adults, but I hope that we will be able to use that quadruple therapy rapidly in kids also. Because it obviates the need for the LA freezes in many instances. What's the frequency that it needs to be given? The drug is dosed, how frequently? It's intravenous dosing, I think, once a week. Wow.

But they are working on a subcutaneous formulation of it. Because of course intravenous, but these kids are used to something. Yeah. I mean, these kids don't have veins. I mean, you're basically putting pick lines in kids to give them treatment or something. Wow. So there is a small but vocal cadre of people out there who kind of refuse to believe that LDL is causally related to AACVD, or another sub variant of this group who believe that it's only causally related to AACVD in the context of metabolic illness, but if you're metabolically healthy, then LDL is not problematic. Based on your knowledge and experience with FH, which spans the spectrum

of metabolically healthy to unhealthy people, how likely do you think that is? These patients that you mentioned before are always used as the stick to beat people like me, because they say, if LDL is truly causal, it's impossible that some people don't get heart disease while having FH. I try to explain that most genetic diseases are modified by other environmental and genetic factors, but someone, these cholesterol critics dot org, it's a website of a strange bunch of people that absolutely don't want to accept that LDL cholesterol is bad, but my experience with FH, my entire career, I've seen these families, I've worked a hundred hour weeks for years to find all these people and we were able to find the largest cohort on the planet of hetozygous phage. And these stories are all hard breaking. So for me, it is so simple because these people have one thing, one, a mutation in

a single gene that doesn't do anything else than raise LDL cholesterol and they drop dead, you know, when they're like 25. So for me, I don't even listen to it anymore. Yeah, I mean, it's the sort of Mendelian randomization also makes that clear because it doesn't just include FH. It goes all the way down. It might response to people when they point out the observation that there are some people with high LDL cholesterol or high APOB who don't have coronary artery diseases. There are also people who smoke their whole lives and don't get lung cancer. And by the

way, there are people who never smoke, who do get lung cancer. Neither of those facts remotely diminishes the causal case for smoking and lung cancer. I couldn't agree more Peter, absolutely. And I find it also because of course, the FH argument was always the scientific argument of proving that LDL cholesterol if it's elevated sits at the core of ethyrogenesis. And then of course when it became clear that there were a few people among these families who could actually live without a problem, they used that as an argument. But I completely agree the smoking is a very good example, but there are many more. So, let's pivot now to a class of drugs that I discussed at length with Dan Raider, the

C-TEP inhibitors, because you're very involved in not just the latest of these, but potentially the first one that really appears to have a shot at working. So let's back up for a second and for folks who either don't remember the podcast with Dan or didn't hear it, let's provide an explanation of what CTEP is and maybe a little bit of the sorted past of the CTEP inhibitors and you know, what is prologue to where you are now? The prologue, unfortunately, is very long, Peter. And it's one of the best examples of how big pharma can make big mistakes. So, the CTP protein was discovered by Philbater, the Australian KOL,

that's now retired, but he discovered this protein, and I think he actually discovered it in rabbits. And why did he look in rabbits? Because if you give a rabbit, ake yolk or cholesterol, that rabbit gets atro-scarosis. If you do the same diet to a mouse sclerosis. If you do the same diet to a mouse or to a rat or a hamster for that matter, they don't get athero. And so it was extremely interesting what made a rabbit different from other rodents. And that is CTP. So a rabbit has CTP. So all strategies to lower CTP were tested in that New Zealand white rabbit, like SIRNA, gene therapy, small molecules, antibodies against CTP. And in all instances, you could cure the etharo with lowering of CTP activity. At the same time, it became obvious that in Japan, there are many people with a mutation in CTP,

so they have very low CTP. And initially, the first report said, these people live longer than we do, and they are free of coronary disease. So then loss of function of CTP became a longevity gene. It is still by many people called a longevity gene, because if you don't have it, you live longer, you have less Alzheimer, you have less diabetes, and in general, you are just simply more healthy. Sort of like PCS, canine loss of function as

well, also a longevity gene. Yes, you don't need that. You don't need pieces, can I? The theory is is that we all went through the evolutionary funnel about 10,000 years ago during the last Ice Age. There were very few humans alive, especially in the north, and they went through the evolutionary funnel where everything was directed against being thrifty. People that could absorb the last calorie out of a mammoth were favored. And actually, we now think that those genes that we selected during that evolutionary funnel are now bad for us. Like we don't need PCS-K9.

We don't need CETP. We probably also don't need NGP TL3. And so all of these genes were meant to conserve energy and to conserve cholesterol. And so what CTP does is a very simple thing. Is it grabs a cholesterol-estorm molecule from an HDL particle, CTP sits on the HDL particle, like a little cap. It's a curved protein that sits on top of a sphere, and it has an opening and it sucks a cholesterol molecule out of HDL, then that particle collides with an LDL particle, and there's a little tunnel, and it spits the

cholesterol-estomolicule straight into LDL. So the consequence of that is, is that HDL cholesterol goes down, and LDL cholesterol goes up, which in the days of very active LDL receptor activity was a great idea, because then all the cholesterol went back to deliver, and a cholesterol molecule is very expensive to make. It costs 2780 piece. In a nasty environment like the ice age, you want to conserve that molecule. And the best way of conserving a cholesterol is by sending it back to deliver and 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 with it.

But in a situation where our LDL receptors are not that active anymore, adding cholesterol to LDL is not a very good idea. And all the Mendelian Drenerimization Studies have shown that people with high activity of CTP have more heart disease, more heart failure, more kidney disease, more diabetes, more Alzheimer, blah, blah, blah, the whole works. And so Pfizer was the first to say, ah, a torvastatin's patent is going to expire within a few years. Let's have another a torvastatin.

So we make a C-tap inhibitor called Torsetropip. I was involved in all these large trials. So I was on the steering committee of the Avesetropip trial on all of these trials, except revealed that was done by Oxford. But Pfizer did a phase two, and in the phase two, after four weeks, blood pressure went up a little bit. And then comes the big pharma mistake. Why do we care about a little blood pressure increase if HDL goes up by 70%. They didn't understand why the blood pressure went up and they moved the drug into phase 3. That is a fundamental mistake if you don't understand a side effect in phase two, you don't move drug

into phase three until you've understood it. But listen, it was my fault also. I was on the executive committee of the outcome trial with Torsetra Pipp and we all thought, oh my God, this is gonna, you know, this is gonna be the next fantastic wave of drugs in cardiovascular disease. But that drug killed more people than it saved. I remember in September of 2006, exactly the street I was standing on in the financial district of San Francisco when the trial was announced that it was being halted and I was so, I mean, to quote the planes trains and automobiles, if I had woken up with my head sewn in the carpet, I would have been less surprised than that outcome,

because I too was so optimistic based on the HDL cholesterol increase, even though it was clear this trial was kind of a stupid land grab from an IP perspective on the part of Pfizer, you know, it had to combine it with a Taurus statin and all that kind of stuff. Exactly. Putting that aside, I thought this is going to be a world beater and it turned out to be an enormous failure.

Then everybody was fired except the basic scientists who got the assignment to understand what happened. And they, it was so interesting because they took the drug and they infused it into a rat. Now a rat does not have CTP, but the blood pressure went up in 10 minutes. Boof. So that told everyone that this is a drug that has an off target effect. Fortunately has nothing to do with CTP, but the drug actually raced straight into your adrenals, where it promoted aldosterone production, cortisol production. It raced into your endothelial cells, where it promoted endothelial in one, which is like

an angiotensin-2, terrible vasoconstrictor. And all of that led to water and sodium retention, low potassium, high blood pressure, because these were secondary prevention patients, and you don't want a drug like that in a secondary prevention patient. So that was the most unfortunate beginning of a new story in our field, the wrong drug. You know, it's so funny. This was not too long after another epic failure, but one that I would argue resulted in a drug being removed that shouldn't have been removed, but instead required a little bit more work to determine who the susceptible individuals were. And of course, that's the drug viox. I don't know if it had the same name in Europe,

but truly a remarkable cox2 inhibitor in In a league of its own, makes celebrex look like drinking water in terms of its impotence. And there's no question that there were a subset of patients in whom viox slightly raised blood pressure and led to a small increase in events. But I think it was mercury that was the company that made viox. There, again, I don't want to over speak, but I think they're arrogance

and refusal to act in a timely manner resulted in just the loss of a drug that I think to this day where we'd be better off with than without. There's just something about Big Pharma where they are often deserving of the reputation they have, not always, but often they are their own worst enemies. Yeah. This was a prime example of how can you make such a mean I'm now a drug developer myself. So with Michael Davidson whom I greatly admire the idea that we would push a drug in phase three while not understanding a side effect in phase two is just incomprehensible. And then what's interesting and not many people realized that Peter then came Roch. Yes. And this is what this was a Dalcetra.

Dalcetra. This is a Zephyr. Dalcetra bib. That drug was extremely important for all the signs because that drug only raised HDL. It was a very weak CTP inhibitor. It only raised HDL by 30%. And there was no effect on the couple of myocurve in the cardiovascular outcomes. So what? So whatever. And what people didn't realize that drug was the end of the HDL hypothesis. Because there was no effect on LDL, no effect on Epob, no effect on non-HDL, but there was a 35%

raising of HDL cholesterol, and that did not translate into one less heart attack or stroke. So that ended the HDL hypothesis in a way. Yeah, and I think we would only go on afterwards to see two Mendelian randomizations. One, looking at genes that raised HCL cholesterol, one, looking at genes that lowered HCL cholesterol, neither were found to be causally linked to AACBD. So, when I hear people tell me that their high HCL cholesterol is protecting them from coronary artery disease in the presence of high LDL cholesterol. I have to restrain myself in the context of CTEP inhibitor failure, number one, two, three, four, five, six, seven, and Mendelian randomizations that, as you said, completely fly in the face of this hypothetical belief system.

But what is extremely interesting is that in those days, we didn't understand that you really need to lower LDL cholesterol with a CTP inhibitor to see an effect on ACVD. So Merck, then actually was the third, they got a drug called anaesthetrip. And by that time people weren't sure anymore whether they had to power an outcome trial on the basis of the HDL cholesterol increase or the LDL. And Merck said to Oxford, just make the trial large enough and they did a 30,000 patient trial, which is I think until now still the largest cardiovascular outcome trial ever. 30,000 patients, but they overestimated the LDL lowering. The drug only lowered LDL by 17%.

The baseline LDL in that trial was 60 milligram per deciliter. So the absolute LDL was 11 milligram per deciliter. That predicts, if you put it on the metagridinal line, that predicted a 9% reduction in mace and that's exactly what it got. So that trial validated that CTP inhibition only lowers heart attacks by virtue of its LDL lowering and that it answers to the same law as statins, zidemipe and PCS canine monoclonal, it is on the same regression line. So then, Michael and I understood that what we needed to find was a C-Tep inhibitor

that didn't have the off-target effect of torsetropy. That was way more potent than torsetropy and lowered LDL robustly so we could repeat the anaesthetripe trial but then with a much bigger effect size. And we found that drug at Mitsubishi. Before we talk about Obis etropib, I want to kind of highlight two things you said. The first is you have literally provided the most lucid evolutionary explanation for our species-wide transition to the preservation of APOB. I have to be honest with you, I had never heard it explain the way you did and it makes so much more sense than any other

kind of teleologic or evolutionary explanation. So I just want to make sure I heard it correctly because I'm going to use it often. I'm going to be the most boring guy at the parties now because I'm going to use this story to explain it. It's called the thrifty gene hypothesis and it's more often used to explain, for example, that people in Asia get type 2 diabetes at a much lower BMI than weak occasions, because they've gone through much more famine when the rice

failed huge famine in the far end. Yeah, yeah. And I've always been familiar with those arguments as they pertain to diabetes and obesity. I just had never taken the additional leap of, hey, I know it takes 27 ATP to make a molecule of cholesterol, but I never made the additional leap, which was think about how expensive that is and in an environment that is so rescores constraint, which up until 150 years ago, we were. So we spent hundreds of millions of years in an environment where preservation of resources was the second priority only after reproduction,

that of course we would be so effective at LDL clearance and therefore of course we would want to be in the business of shuttling as much cholesterol from HDL into LDL via RCT because we knew it was going to a good place. Back to the liver, it would be circulated as bio. We would ultimately recirculate that pool, we could make more hormones, we could digest more food stuff. Yeah, it all makes sense. And then low and behold, uh, about an effective like 150 years ago, it was not such a premium on that now. And we've got more than enough cholesterol to spare. And that thing, that gene that we worked for millions of

years to preserve now is biting us in the ass, just like the same genes are around adiposity and insulin resistance. And there is a very interesting additional piece of evidence is that if you make a mouse look like a human hetozygous fH, and you infect that mouse with bacteria and compare the results of infection with bacteria in the non-FH mouse, the FH mouse is better resistant against bacterial infection. And so the theory is, and we've seen that in our pedigrees, is that FH in 1860 was not such a severe disease as it's right now, And maybe there is so much FH because again, in the ice age,

having high LDL might have been an advantage as a protection against bacterial infection. These two things converge. Yeah. And think about how amazing that is in terms of a parallel to ApoE4. Exactly. Like, this is the exact same story as apoe4, which basically was the only apoe isoform we had until what 200,000 years ago. Yeah, something like that I think. And it offered remarkable protection against infections. And of course, it's only today, A, with our longer life, but B, I would argue with all of the insults that come with our longer life, that Apo E4 is such a predisposing factor to both cardiovascular and neurodegenerative

risk factor. Okay. So first off, that was an amazing explanation of the story. So that was actually also, I think, a fantastic prologue for those who missed the discussion with Dan. So let's recap where we are with Obacipitrid, right? That's the that's the current one. Yes. So it is how potent, I guess you've done things too. Yeah, I don't listen. I am still a scientist and I don't want to sound like a salesman, but

we were lucky finding this drug in Mitsubishi. Yeah, so tell us more what that means. So, health folks understand, how do you find a drug? How is drug discovery done? How did this thing come about? So, I am a consultant to many biotech companies and sometimes companies ask me to look at the pipeline and see if there's anything good or bad in it. So, I was invited by Mitsubishi to look at a number of things

and I saw the phase one data of this compound that was still called TA 8995 and I saw that at 1 milligram that drug lowered LDL by 27%. Now remember, Dorsetopip was used at 600 milligram and it didn't do anything on LDL. So I thought, holy moly, this drug is very potent. And then I looked at the CTP inhibition at 10 milligram, which is a dose we're now using, there's a 97% inhibition of CTP. So it's simply in that sense, and surprisingly potent C-tap inhibitor. And that translates into an LDL lowering of about

50% on top of high intensity statins and an HDL increase of 165%. Now you have to control yourself when you see those numbers, because you know that the HDL cholesterol increase is not going to do anything for heart detection strokes, but Michael and I are not only working on this drug to develop it. We're also scientists and we wanted to understand all the genetic and epidemiology and Mendelian randomization data. And so we've gone far beyond heart disease with this drug. And so we've gone far beyond heart disease with this drug. We're looking at Alzheimer, age-related macular degeneration,

septicemia, and diabetes. Because if you really inhibit CETB, you not only stop the transfer from cholesterol, from HDL to LDL, but you completely change lipoprotein metabolism and you force the liver to produce more Apple A1. You and I can, I think, agree on the fact that Apple A1 is a fantastic molecule, because it is the molecule that ABCA1,

the cholesterol pump on the cell membrane, recognizes and actually exports cholesterol to. So that was the first. And then we also know that if you produce lots of Apple A1, you produce lots of pre-beta HDL particles, the small HDL particles, and these particles suck cholesterol out of peripheral tissues. Now in endothelial cells are macrophages that's probably good, but what's much more interesting is that they suck cholesterol out of the beta-idol cells in your pancreas. And you undoubtedly know that with life, if you're a type 2 diabetic, more and more of these cells die till the point

that you become insulin-dependent. That is because of the lipotoxicity of that cell. That cell takes cholesterol, can't export it. The steriles are oxidized. They become pro-inflammatory, toxic. The cells go into apoptosis and they die. So that is all red. And this is proven now for all four CTP inhibitors.

So all four CTP inhibitors in their album trial had less diabetes in the treatment arm than in the placebo arm. And we've published that in a meta analysis. But half a year ago, just to be sure I understand, John, is that because you think, regardless of which of the CTEP inhibitors we saw, we were seeing more heterotypic exchange between the APOBs and the APOBs. Okay, so let's explain for people. Tell them the difference between homotypic exchange and heterotypic exchange, which is pretty easy to define, but more importantly, clinically, where these are occurring and why these are leading to the outcomes that we're about to get into. So the sequence is probably this.

You stop the transfer of a cholesterol molecule going from HDL to LDL. That will make HDL higher by definition and LDL lower. Now, then has done stable isotope turnover studies and have shown that the reason for So these LDLs actually get 50% lower, which is a huge drop, because the liver up regulates and what can the liver up regulates their LDL receptors. At the same time, these large HDLs take EpoE on board. And as you know, EpoE is also a ligand for the LDL receptor. So the large HDL particles are also cleared by the liver. And the liver does that because it produces large amounts of Epoe1, which kind of disturbs the balance. So there is a new

equilibrium between removal of lipoproteins by the liver and production of small HDL particles, but that only happens if you almost completely knock out CTP. So you have to really inhibit it by about 90%, which is very close to the homozygous patients in Japan. They also have half LDL and about a triple HDL and every other thing that I just described. So it's for me and I think also for Tom Deis being a people that really know lipids, this is extremely interesting because it is complex. It is complex, but until now it is extremely exciting because there are two groups in the world, so this is the diabetes part, you know, where you suck cholesterol out of the beta cell.

Then there is a septicemia part that I never really knew about. There are two groups in the world, one in Vancouver and one in Leiden, that have shown that if you're born with a loss of function, variant in CTP, you are much better protected against septicemia. And not a little bit, but like mortality, big effect. Actually, there are multiple presentations this year of these two groups, and they of course want our drug to test it in septicemia. Let me make sure I understand something.

And I wanna go back and ask a question about FH to bring it back to that. Is there any evidence that FH patients untreated have a lower mortality due to septicemia? It's not great science, but there are some indications, but most of that work is done preclinically. So it's not as straightforward as, look, if you have high peripheral cholesterol, you have more precursor to make corticosteroids, and therefore support immune function in the time of sepsis. It's much more complicated than that. Now, it's way more complicated, and it's most likely has to do with the scavenging function

of lipoproteins. So if your CTP is low, when you get septicemia, your HDL stays high. And it's very likely that the HDL particle functions as a sink for endotoxins and everything else. And so having a high HDL and a constant high HDL during septicemia is a very good thing. And I on a recent podcast shared that I used to witness the opposite in the ICU, which was a drop in HDL cholesterol. Yes, you always witnessed that. Yeah. And that would that would actually be a poor prognostic indicator. Not necessarily poor. It's just

that's the normal indication. Yeah, yeah. Yes, if your HL drops like to nothing that's a poor prognostic indicator, you are protected against that drop. If your CTP activity is low, because it's like having a CTP inhibitor on board, which stops removing cholesterol from HDL.

Yeah, so again, this is a function issue that is not just a blind phenotype issue. The sort of paint by numbers approach to this problem is high cholesterol good because it's more precursor. No, no, it's C-tep inhibition good because you have a bigger sink to dispose of toxic waste. Absolutely, that's it. a bigger sink to dispose of toxic waste. Absolutely. That's it.

So that is the septicemia part and the diabetes part. Now the diabetes part is proven in a meta-analysis. For example, the roast drug, and that's so interesting. The roast drug only raises HDL. Doesn't lower LDL. No, zero. And so it's protective effect against diabetes can only be connected biologically with the HDL, of course. And so it's now thought that if you raise HDL with CTP inhibition, you protect the prunkios against apoptosis. It's an effect of about 16 to 20 percent in the new onset type 2 diabetes between placebo

and active treatment arm. So it's not like a tiny effect. It's almost as big as the negative effect of statins on diabetes, which is also at the highest dose 15 percent or so. So let's just make sure again, we bring it back to this idea because am I correct in saying that Obesetra Pibs, the first CTEP inhibitor that impacts both hetero-tipic and homotypic exchange? That is very hard to say, Peter, because there is not much work done with the older CTP inhibitors. Dan Reader has done a huge amount of work with the Merck anaesthetopib. He has, for example, shown that HDL particles from anaesthetopib treated patients have more

cholesterol efflux from macrophages. He has shown that SRB1 is upregulated in the liver by CTP inhibition with that drug. So he has done a lot of that work with the other drugs, not so much. Not so much. Okay. This is pretty exciting. A sort of student of this world would have to be forgiven for having a little bit of anxiety and fear about being too optimistic here, right?

This is one of those things where we've been burned on every one of these, right? There's a track record of four or five consecutive failures, some more epic than others, perhaps none more epic than Pfizer's. And yet, let's just say like if you were a Wall Street analyst trying to get your arms around this, you'd have a really hard time getting excited based on how many times you'd been burned, but we're not stock analysts, and we're really just trying to come at this through the lens of science. What would you say is the greatest risk that this does not pan out?

So let's explain what has, what we know so far. You've completed phase one. So there's no, there's no toxicity. And phase two, and phase two, and you had four phase two trials. We have one, two, three, four phase two trials. Yes. And we are now fully in phase three. And in fact, all our phase two trials will be fully randomized this year. So we have gone, we've pulled every plug we could, we've started the outcome trial at the same time as our lipid trials, because we of course realize that what we need to show is robust LDL lowering, robust non HDL lowering, robust Apple B lowering, and then we need to show safety. So,

blood pressure affects nothing, good safety, good tolerability. It's a tiny pill at 10 milligram pill. And then, of course, at the end of the day, we also need in the future to show outcomes. In a cardiovascular outcomes trial, of course. But I have to say that until now, Peter, this drug is well tolerated. We haven't seen any side effects in phase two. And it lowers LDL by half, which makes it just as potent as the injectables, but then in a 10 milligram pill, when we first saw these LDL results on top of high intensity statins, I was kind of amazed at this.

Yes. So I don't want to get too far ahead of ourselves, but I'll just assert something here, which is if this pans out to be as good in large phase three studies as it has been in phase two, the only thing that would stand in the way of this displacing every statin on the planet is cost because you'd have equal or better liquid lowering efficacy. And instead of having a small increase in the risk of type 2 diabetes, you would be patently reducing that risk. We're going to talk about the brain in a moment as well. There may even be some benefits there, but let's put that aside for the moment. So there's a lot riding on this. It's cheap, Peter.

It's very cheap to make. Well, I was going to say, given that it's not an injectable monoclonal antibody, this is cheap to make. And yeah, it's actually very cheap to make. I think this is public knowledge. It will cost $36 per year to make this drug at the time when you have lots of patients. So, what's called peak sales. So the drug is cheap to make and that will allow us to price it

reasonably and ethically. And that is something that Michael and I have always wanted is to have a drug that lowers LDL that you can use on top of a statin or in a fixed dose combination with a zidimipe that robust that lowers LDL that you can use on top of a statin or in a fixed dose combination with a zidimipe, that robustly lowers LDL and Epob has little or no side effects and is easy to put in your pillbox because the vast majority of my clinic in Amsterdam, they have pillboxes and they are a bit afraid of a needle and they want an extra pill to get their LDL done. They are a bit afraid of a needle and they want an extra pill to get their LDL done. So let's talk about the three trials. Just to be clear, the three phase three trials, you have Broadway, Brooklyn, and prevail.

So Broadway is 2,400 patients one year. It's looking at drugs. ASVD patients. ASVD patients. These are high risks. This is secondary prevention in people who are on their existing, maximally tolerated lipid lowering therapy. And you're going placebo versus drug.

It's not open label, correct? Yeah. No, no, no, it's placebo controlled. Tutu on randomization. And is the belief that this trial in 52 weeks with 2400 patients is significant enough to see a different in MACE or is this not powered for MACE and it's just a biomarker study. No, it's not powered for MACE, but of course every phase T-Trial, whether you've alirocamap, avalocamap, inclyceran, or even bempidobog acid, we are adjudicating events.

We expect about 120 events in its entirety. And of course, we hope to see a trend. That's what you hope. Yeah. So in other words, rather than 80, 40 between your two to one randomization, there may be a significant difference, although you're not really powered to it unless the difference is significant. We are not allowed to do statistics.

The FDA does not allow to do statistics, but this is just a scriptive and exactly like in Clizoran, in Clizoran had about a 30% difference in events if I can, if I remember correctly. And that at least gives you an indication that it's moving in the right direction. So every everyone hopes for that, of course. Okay, so then you've got Brooklyn, which is a very small trial, but it's also... FH, yes, exactly. That's in heterozygous FH, 300 patients, same thing. Same thing. And then prevails the big one, right? So that's where you've got 9,000 patients, and are these people with existing ASCVD as

well? Is this also secondary prevention. Yes, it's hardcore ASCVD and we've even entered a lot of risk and haunting factors into this trial because we understand that the higher the risk, the easier it is to show a benefit. And we also strive for a baseline LDL of around a hundred. benefit. And we also strive for a baseline LDL of around a hundred. Because if your baseline LDL is around a hundred and your LDL lowering is 50%. Then your absolute difference is 50 milligram per deciliter. If you plot that on the CTT matter regression line, you have a 27% major reduction, You have a 27% maize reduction, which of course you can do because there will be

People on off-drug there will be people who are gonna take a PCS canine monoclonal But at least we are very sure that it's going to be more than 20% maize reduction and Aside from not having coronary artery disease, what are the exclusions for prevail? If your LDL is below 55 milligram per desoliter, so we have adapted prevailed to the new American College of Cardiology guidelines. So one of the things that I've talked about, I think on this podcast, is that when Fourier and Odyssey were launched, especially Fourier, I was personally quite skeptical. Not because I didn't believe PCSK9 inhibitors would work.

I really believed PCSK9 inhibitors were going to be a home run. I believed that they were going to be incredibly safe. So all these things that ended up being true, I actually believed. But I thought the trial would fail. Because the patients were coming in. This was also secondary prevention. So a very similar patient population to prevail.

These people have an average LDL cholesterol of something like 70 milligrams per desoliter on the way in. So you're taking people who are heavily drug to LDL cholesterol of 70 milligrams per desoliter, randomizing them to PCS canine inhibitor versus placebo My thought was you can't do that study long enough to see a difference Well, I turned out to be completely wrong, right? That study was halted at something like 3.2 years But do you worry about that risk here? Which is you've got patients that are so heavily medicated? Yes, you're gonna exclude them if they're're down at 55. But look, you're going to have a lot of people at 70 milligrams per desolate.

Yeah, but it's interesting is that we have already randomized a very robust number because we expect to be ready before the end of the year, but 9,000. So you can imagine that we already have a substantial amount of people. And baseline LDL is still exactly where we wanted around 100 because we have actually kind of promoted the inclusion of high LDL patients into our trial. In our discussions with the sites and everything and what was another very big mistake of Fourier was that it was it was not 3.2 but it was 2.3 years. Oh gosh. I got my numbers mixed up and it becomes even more. Yeah, it doesn't matter. It does a 2.3 and that was too short. That was too short. So we've said after our last patient goes in, we at least want to have a two and a half year

follow-up. So that determines that your trial because of course everyone before that already has follow-up and then you add another so we think that we'll have a median follow-up of three and a half to four years and that's really long enough to see the full effect of lipid lowering. Is is prevail being run in Europe in North America? Yes, absolutely. Canada, North America, South Africa, Europe, Eastern Europe, Western Europe. Any other side effects show up in phase two? Obviously, you're not seeing insulin resistance, you're not seeing any muscle soreness, any of the typical statin related side effects, any GI side effects, anything,

or is this truly a zero? I hate to sound like a salesman. We have a paper in the nature medicine, lancer and we are submitting our rose to, which is our fixed dose combination with a zidemipe to another very good journal. And so you look at the tables, there are no side effects. We have not identified a single side effect related to study drug until now. Now, of course, that will change

because in phase three, the numbers are bigger, but in phase one and phase two, we have seven phase one studies and four phase two studies. There's nothing. By the way, which was also true for the Lily C-tap inhibitor, the Rose C-tap inhibitor, and the Merck C-tap inhibitor, and there were none of these three had side effects, 60,000 patients in outcome trials.

So the drugs, if you discount the Pfizer misery, the rest of them was very safe. Yeah, so in that sense, from a side effect profile, we're really moving into a world where between Bempendoic acid, Zedemib, potentially Obisetropib, and PCSK9 inhibitors, you've talked about a class of drugs that don't have side effects. It's really the statins, which obviously do have side effects,

although in relatively fewer people than is generally perceived, that kind of give the overall class a bit of a bad name in terms of side effects. Yeah, there's still, you know, books out there like the cholesterol myth and statins are toxic. And it's interesting because in people that really need it, like severe heterozygous FH, you see a lot less statinentorids than in people in primary prevention that just have it as a lifestyle drug. So there is a large psychological component

to all of this undoubtedly. So do we see any benefit on LP little A reduction. We do come up 56% more than with a PCS K9 inhibitor than yes. Okay. So say say more about that. So again, then radar, you know, he he's by life saver. So then did a stable isotope study with anesthetialib and found out that that CTP inhibitor inhibited the synthesis of Apple Little A. Now how that is possible I have no ideal because I cannot connect an intercellular synthesis of a protein to a drug that sits on an HDL particle in your circulation. So there must be a link that we still don't understand. So he, but he, that was a stabilized up study, published in a good journal, he's going to do all of that again for us.

So we are going to do a stabilized up study with Dan for Apple B containing lipoproteins, and we're going to look at Apple Little A. But in our rowstrial, which was the nature medicine publication, LPDL A went down by 56 percent of the 10 milligram dose and 43 on the 5 milligram dose. What's interesting is that other CTP inhibitors lower LPD delay by about 20%, but they are about one third of our efficacy. So it feels like the LPD delay lowering is in conjunction with the LDL lowering. But again, sorry, Peter, I can't explain this. I can't. No, no, it's amazing. And of course, for those listening with elevated LPL

in LA, which of course is hands down the most common genetic finding that leads to premature AACVD. I mean, if we know that there are a few thousand people that are, you know, listening to this who have FH or some trait, there's tens of thousands listening who have elevated LPLL A. Is impressive as a 50% reduction is? We don't yet know if that's clinically enough to reduce outcomes. And that's where I still think I have not had Sam Tameka's on the show, but remains to be seen if the ASO inhibitors 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 something else that we didn't talk about, but I want to just remind the audience of the Mendelian randomization. So we go back to the observation,

which is that C-TEP activity is largely genetic. And we've already talked about the fact that there are some people who basically are C-TEP hypofunctioning individuals. These people tend to live a very long life. They have less heart disease, they have less Alzheimer's disease, they have less diabetes. Less heart failure and less renal disease also.

Oh, I didn't know about the renal disease. Okay. So what we so we basically say look in addition to apoe2 as a longevity gene, Foxo apoc3 hypofunctioning we can now add hypofunctioning C-TEP to the list of things like hypofunctioning PCSK9. When you go and look at the MR the the Mendelian randomization, it makes it very clear that for every one microgram per milliliter decrease in a genetically determined C-TEP concentration, we're going to see about a .1 millimole per liter reduction in LDLC about the same reduction in triglyceride, this enormous 2 plus nanomole per liter reduction in LP little A, that 0.2 to 0.25 millimole per liter increase in acyl cholesterol, etc., etc.

But one of the things I never realized was you're also seeing a reduction in blood pressure, about 0.2 millimeters per mercury, which again doesn't sound like much until you realize that this is just normalized to one microgram per milliliter. You also see a .1 roughly millimole, per mole change in hemoglobin A1c. In other words, this is a potent anti-hypertensive agent as well. What in the heck explains that? Yes, so there's absolutely no explanation for that. Yes, so there's absolutely no explanation for that. It was by the way very interesting because those data on blood pressure were already known at the day of Torsetropib, which should have been a red flag to these guys, right? Exactly, which should have been a double red flag to these guys that if you inhibit CDP, you can't, the blood pressure increase has to come from something else.

Okay, but no, no one understands the blood pressure at all. There's no, because CTP is made by the coop for cells in the liver and it gets synthesized, excreted. It sits on the back of an HDL particle. One in 10 HDL particles have a CTP protein on their backs, and the half-life is actually the half-life of an HDL particle, which is about a week. So it's a very simple protein. It sits in your circulation or HDL does what it needs to do and how on earth it can have anything to do with blood pressure, I would surely not know. The relation with brain lipid metabolism, there's much more known about that now than let's say two years ago So there we're making great strides in understanding how

loss of function of CTP influences brain cholesterol metabolism. That's Fantastic science. So I know I promised you that I wouldn't keep you up too late in the evening in Amsterdam, but I just don't see how we can end this podcast now without going down that rabbit hole a little bit. Would you grant our listeners a little bit more of your precious time if you've been generous in sharing? Okay, thank you, John. So if you look at late onset sporadic Alzheimer, which is the vast majority of

Alzheimer's patients, 65% have an EpoE4 molecule on board. They're either E44 or E3E4 or E2E4. So they have an E4. If you have E4E4, your risk for Alzheimer is 16 times higher than when you have E3E3. And if you have E3E4, your risk is about 4.5 times higher. We now begin to understand why carrier ship of Apple E4 is so bad for the brain. Apple E4 is an insufficient molecule to get cholesterol out of cells in the brain that have too much or bring cholesterol to cells in the brain that have too little. So it fails on both accounts.

It is not a good acceptor of cholesterol and it's a bad bringer of cholesterol. And so if you are E4 and those cholesterol abnormalities accumulate over life. You actually get sterile accumulation in neurons and if you have steriles in a cell too long, they get oxidized. I mean, everything oxidizes in us. We rust like anything else if we are exposed to oxygen, we get oxysterals. Oxysterals are what kills cells. It gives a pro-inflammatory signal. It drives cells into apoptosis.

It is the worst thing that you can have. Now, an oxysteral is not much of a problem if you have a functioning particle in your brain that sucks the steriles out of the cell and then converts it to 24 hydroxy cholesterol and that gets true to blood brain barrier to your liver up into bile and it's gone. That whole normal process where the brain needs a lot of cholesterol for myelonization, building synapses, building these crouts and at the same time, if they have too much, they want to get rid of it fast in order not to get is all wrong in an Apple E4 carrier. So what is the protein that can help here? It's only one protein, Apple A1. Apple A1 can take over all these functions of EpoE4.

And how do you get EpoA1 in the brain by raising it substantially in circulation? Because unlike EpoE, EpoA1 can get through the blood brain barrier because it's small enough. And there's very likely a specific receptor that actually pushes it through brain cells. And which drugs do raise Apple A1 by far the most CETP inhibitors?

So that is the connection. So these large HDLs, they acquire Apple E because they get larger and they lose their Apple A1. And we think and we have preclinical already some evidence for that but we're doing a trial in humans where we tap CSF to look at Apple A1 that if your Apple A1 concentration goes up in the circulation enough, you'll push it into your brain and once it's in the brain, it takes over the function of this dysfunctional Apple E4. It's a fantastic story,

Peter. The nomenclature makes this complicated. So I guess, let's make sure people understand what we're talking about. It's always a problem when the gene and the protein have the exact same name, right? At least with Lp little a, we have the Lpa gene and then Lp little A, the Lypa protein. But here, it's the same name. We denote it differently, right? We use all caps versus not and talix and all that. But when we talk about the ApoE4 gene having these three isoforms, two, three and four, you're going to get six different combinations of them.

But what you're talking about is the protein. You're talking about the thing that is made by the gene. Again, what's just another remarkable insight into the complexity of biology is the protein apoe, which is not designated two, three or four. It's just the protein apoe, the one that is made that is transcribed and translated by the e4 isoform, I believe it only differs in one amino acid from the wild type. It's a very subtle difference, right? It is. It is an arginine for glutamine, I think,

or something at amino acid, one 52 or one, one eight. I can never remember it. I always thought it was 127, so yeah, we're one of us is wrong, but yeah, whatever. Yeah, well, I'm sure I'm wrong. It's only one amino acid. And that changes the three-dimensional confirmation of that protein completely and makes it basically a lousy cholesterol acceptor and transporter. If you carry an E4, you have like a list this long

of things that go wrong on your brain. It's prone flammatory. It is insufficient in lipoprotein metabolism. It is no longer a shaperone for beta amyloid. You know, it's like a very long list. And it's terrible for for people that have E4. I think one of these Hollywood actors actually knows that he is, he is an E4 carrier. He's that that athlete. Chris Hemsworth. Yeah, he's that athlete. Chris Hemsworth, yeah, he disclosed this during the, the limitless series, which, which I think was,

was really valuable for a lot of people to see, to bring a lot of awareness to this. And by the way, I've made the point many times that it is very valuable for someone like Chris to know that he has APOE4, because the earlier you take steps to prevent the exacerbating risk factors, the better your odds. I mean, the one thing that's important to point out, you open this discussion by explaining the risk factors.

I look at data that suggests it's a little less than 16 and fourfold. I think it's sort of maybe closer to 10 fold and two fold, but we don't need to worry about that. There's no question. It's high risk, but it's important to note, it's not deterministic. No, it's no deterministic. And in fact, it's far less penetrant than FHs. Yes, it is. There are lots of people walking around with EpoE4 that are not getting Alzheimer's

disease. And as you pointed out, a third of people with Alzheimer's disease don't have EpoE4. So everything we're talking about here is fair game to everybody. What you said that's interesting that I didn't realize until today was APOA1 can traverse the blood brain barrier. And therefore, if you have a therapy that raises APOA1, you can potentially offset the damage of effective APOE in response to APOE4. Do we have a sense for many of the preclinical work that's been done, or even the early clinical work that's been done, what the magnitude of that can look like?

Where I'm going with this, of course, is how could we begin to quantify the potential benefit of this? Is this something where, as you probably know, Mike Davidson also very involved in the clothos space, right? Also very involved in looking at the observation that those with clotho KLVS variants seem to have almost complete protection from their apoe4 gene. It's remarkable finding. Yeah. So there is one large Mendelian randomization study in E4 carriers and which gene can protect you loss of function of CTP.

So we already have Mendelian randomization data in humans that low CTP protects an EpoE4 carrier against Alzheimer's. But what you just asked me is can we have an effect size here? We are doing a proof of concept trial where we tap Cereospinal fluid and we look at, I mean like 50 biomarkers, because what we hope is that Apple A1 goes up in the brain. That the consequence of that is that the cells are going to normally synthesize cholesterol, so the Desmosterole and Lahto-Stereole role levels should go up because cholesterol synthesis is normalized

again. At the same time, 24 hydroxycholestyl should also go up because cells are getting rid of cholesterol in a normal fashion and the inflammation biomarker should go down because you basically substitute for this dysfunctional E4. So in order to understand the effect size, we need to be able to make a story where we say dysfunctional E4 replaced by A1, normal cholesterol synthesis is on again, normal cholesterol removal is on again, inflammation goes down,

and of course this proof of concept trials only six months. So there won't be much in Alzheimer's biomarkers. But if we can show that we improve lipoprotein metabolism in the brain, it is a first step into a fascinating journey, I would say. Will you be measuring does mosterol and lothosterol in any of these trials or in all of them? Yes. Yes. No, we in the Alzheimer's trial we do, which is prevail is the one where you're going to know. No, no, the Alzheimer's trial has no name. The Alzheimer's trial is a trial in, oh, it's a fourth trial. It's a fourth trial. Yes, it's a fourth trial. But we have no name for it because it's in a single center in Amsterdam

and it's a large Alzheimer's center, where we have basically mild cognitive impairment, with the diagnosis of Alzheimer's. So early Alzheimer's, we give them our drug, and we seriously measure both blood and CSF by spinal taps. I got it. But you will not be in prevail, for example. Will you be looking at with cholesterol, with this master all levels? We have a lot of spare tubes. So that is definitely something that we have a quite a wish list of things where we want to look at. Well, inquiring knuckleheads like me want to know.

Let's close out our discussion, John, with an explanation of the role of APOE in cardiovascular disease, because APOE gets a lot of attention for what it's doing in the brain. We just had a pretty brief but insightful discussion on that. But I think people are less clear on the relationship of apoe in the heart. So what can we say about atherosclerosis in apoe? Again, apoe for might have been wonderful during the ice age, but now it's bad, because it's associated with higher LDL, it's associated with a more pro-inflammatory state, and it's

associated with more heart disease. Now if people have a hard time believing how it's possible that when you're in EPOE4, that you have higher LDL, the explanation is that Apple E of course sits on VLDL and on VLDL remnants. And Apple E4 actually is a better ligand for the LDL receptor. It's an amazing story, the Apple E story, a better ligand than E3E2. And so especially the chylomicron remnants and the VLDL, so IDL races into your liver and that will down-regulate the LDL receptor and therefore LDL goes up.

Sorry, just to make sure folks understand that because it's a bit counterintuitive, right? This is a little bit of a paradox. It is totally counterintuitive. If you have APOE4 and it's a higher affinity ligand for the LDL receptor, it should mean that apoi4-generated proteins lead to more rapid clearance of LDL. But if I understand you correctly, not LDL. There's no apoi on LDL. Yes, yeah.

Okay. Sorry, sorry. It's all on the remnants and on VLDL. I see. And that's the point. So because it's the remnants and the VLDL, those readily get attracted, downregulate the LDL receptor. So there's less LDL receptor to get rid of LDL. Is that the chain of events? That's the chain of events. But there's much more to E4 than just a little lipoprotein metabolism. There's a like in the brain. There is enough association with other things that are that you don't want. I mean, this chronic pro-inflammatory state that people like Paul Ritker, you know,

has made his life's work of is also associated with an E4 carrier ship. life's work of is also associated with an E4 carrier ship. And does the association with APOE4 in terms of risk vanish once you normalize for APOB, or is there still residual risk based on these other factors such as inflammation that exist and persist once you've normalized for APO 3 versus APO 4 in the context of the same LDLC slash APO B. If you ask Alan Snyderman, you'll say that if you control for APO B, everything falls away and that it's the number of, you can also look at NMR LDL particles, but that APO B is really what drives all our statistics in cardiovascular

disease. It's very interesting, for example, you've seen the Bempodobic Acid data. So the clear outcome straw was on the line of absolute LDL lowering versus major reduction. So where is the room or the space for the CRP lowering effect? If you're on the line, and I really admire Alan him and he has been stoic in his emphasis on Epib for Sholo, and finally, he gets this kind of vindication now, where most people would agree that non-HDL and Epib are a better prognostic marker and a better measure of therapy than LDL cholesterol by the free-dualt formula. But if you ask me personally, Peter, I think that FOE4

has a few properties that you cannot completely knock out, statistically or biologically with FOB lowering. Yeah, I don't think that's a big stretch. And it might be that Allen's view and that view are not completely at odds, right? It could be that those other effects are small enough. That on a clinical level, you would need really large sample sizes and lifetime exposure metrics to see the difference. It also could be that there are other amplifying features. In other words, if you take two healthy people, 1E4, 1E3, with the same APOB, the risk is relatively similar.

But if you take two unhealthy people, type 2 diabetes, naffledy, profound insulin resistance, 1E4, 1 E3, with the same APOB, it could be that those other factors create more of a gap between those people on a Kaplan Meyer curve. I think that that's very reasonable, and I tend in that same direction. I mean, I think for me, part of the takeaway here is just that I'm trying hard not to be excited, right? I think that, as I said before, when you're once bitten twice shy, and I've been a very vocal critic of these trials, meaning that the, you know, the last 15 years of C-TEP inhibitors. And I would say that perhaps I've been too harsh and I've been mostly a critic of the HDL hypothesis and I've relied on the

CTEP story along with the Mendelian randomization as my rationale for that. And in reality, I think that that has created a little bit of a blind spot in my eye towards a more pure biologic understanding. And of course, I'm the last person who should have this blind spot because part of my interest is in longevity. And it's clear to me that C-TEP is a longevity gene, meaning the hypofunctioning variant is as much a longevity gene if not more

than the hypofunctioning PCSK9. So it's with the tincture of embarrassment that this is sort of my mea culpa to say, I have been too down on C-TEP inhibitors and I'm very hopeful that Oba's Etrobeb not only redeems the field, but also gives me something to be excited about clinically in my practice. Thank you very much for that and to be quite frank, I was much like you for a long time and it is, you know, you have to imagine the kind of turnaround you have to make in your head. I was a strong believer in the HDL hypothesis until the roast trial. Then I had to turn around

away from HDL back to LDL and FOB and then understand the blood pressure effect, understand the mistakes in the trials, try to find a drug that didn't have all that baggage. My first New England paper was in 1987. What we did is we measured CTP activity in a coronary and geography trial. In those days, we only had coronary and geography with preface that in. And it was, if you had high CTP activity, you had the worst progression of coronary disease over that two-year trial. So that taught me that CTP was bad. And since that day, I'd wanted to find an inhibitor that was something that I could work with. It's such a beautiful story.

You've articulated it very well, John. And I do hope that at some point, you find the time to write kind of a clinical philosophical paper about science, which is we lost our way. We as the field, meaning like, meaning I'm just observing the field, but the field lost its way in this drug based on the wrong biomarker. We were using HDLC as a biomarker because we didn't have a better biomarker for C-TEP inhibition. And so the initial insight in the biology was right, but by having the wrong biomarker and failing to understand the mechanism of that, 15 years

and I don't know how many billions of dollars, but it's probably approaching 10 billion if not more dollars were wasted. And tragically, by the way, it should be noted some lives were lost. We don't want to lose sight of the fact that this resulted in lives lost during these clinical trials. And that's the price we do pay as a society to advance knowledge. I don't want to suggest that you can never have a loss of life in a clinical trial. But it's just a sobering story.

But if you would forget about everything that happened before, what we won nowadays is strong mandirin vanemization evidence. We want lots of phase one and phase two trials to show that there are no some bizarre side effects. And then you gently go into a phase three with a DSMB and everything. And you don't do a phase two where you see a blood pressure effect and you say, what the hell, you know, that would not be possible today anymore. Fortunately. And that's a good thing, you know. Yes. Well, John, I'm really glad that Tom reached out to you to ask if you'd be willing to be on this podcast.

I'm grateful that you were able to accommodate my time today. And thank you again for the work you're doing. And I'm very excited to follow this story as will the other listeners today. We'll have data on Alzheimer in the summer. Really thrilled to understand what's happening in the brain. Yeah, fantastic. Okay, thank you so much, John, have a great evening. Have a great weekend, Peter. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper

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