#407 ‒ Preventing cardiovascular and Alzheimer's disease: lowering LDL early, APOE4, and promising new therapies | Michael Davidson, M.D.

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If you'd like to receive a free copy of our premium membership, head over to peterattiamd.com forward slash subscribe. My guest this week is Michael Davidson. Michael is a cardiologist, lipidologist, and the founding CEO of New Amsterdam Pharma. He is a recognized leader in lipidology, having coordinated more than 1,000 clinical trials, published over 350 peer-reviewed papers, and authored three books on lipid disorders and cardiovascular prevention. His work spans statins, novel lipid-lowering therapies, omega-3 fatty acids, and cardiovascular drug development. He also founded several biotech companies and clinical research organizations, including the Chicago Center for Clinical Research, Omthera Pharmaceuticals, and Corvidia Therapeutics. Michael also previously served as the president of the National Lipid Association. Michael's career has spanned the intersection of lipid science, prevention, and drug development. And with Obacetrapib, he is now at the center of one of the most important open questions in cardiology, whether CTEP inhibition can finally deliver meaningful reductions in LDL, APOB, LP little a, and ultimately cardiovascular risk. In this episode, we discuss how Michael's family history shaped his career in lipidology and prevention, LDL as a causal driver of atherosclerosis and why it should be treated more like blood pressure or smoking, the history of CTEP inhibitors, why earlier drugs failed, and what makes Obacetrapib different. Obacetrapib's effect on LDL cholesterol, APOB, LDL particle number, LP little a, diabetes risk, and cardiovascular outcomes, how Obacetrapib may fit alongside statins, ezetimibe, PCSK9 inhibitors, and other lipid-lowering therapies, the complicated biology of HDL, brain cholesterol metabolism, APOE4, and the potential role for Obacetrapib in Alzheimer's prevention, and omega-3, fatty acids, DHA delivery to the brain, AI in clinical trials, and the future of drug development for cardiovascular and neurodegenerative diseases. So without further delay, please enjoy my conversation with Michael Davidson. Michael, thank you so much for coming out. It is hard to believe that this is our first meeting in person, given how many years we've worked together electronically and in other ways. Right. Yes. Great to be here, Peter. For folks who might not be familiar with your work, although we've certainly referenced it a lot on the podcast, your work speaks for itself, so you certainly don't need us referencing it. Maybe tell folks a little bit about yourself, starting with what you do clinically. I'm a cardiologist, lipidologist. I run the Lipid Clinic at University of Chicago. I'm a professor, so I see patients actually four full days a month, and that's a pretty loaded prevention-focused practice. What's the path to that? Because lipidology is not necessarily a subspecialty within cardiology, although of course people who listen to this podcast are very familiar with it, and Tom Dayspring has been on a number of times, but what was your path towards that from your training? Were you always interested in prevention? It's a passion because my father died at age 47 of a heart attack. I was 16. I had abnormal lipids, ran into my family, so I got very interested in lipids in medical school. So I did the original niacin trials that went back into the 80s, late 70s actually. And then after training, residency, I started doing research and my fellowship on omega-3 fatty acids for the lipid effects. I was the first one to use fish oil capsules to treat lipid disorders. And then from there, I got involved in all the statin trials. It's been my passion is to be involved in clinical trials. And I'm still a cardiologist, did the usual stuff that cardiologists do, and then focused primarily on prevention. So I opened a prevention center out of my fellowship, along with a research company that did all the clinical trials, and that's been my path ever since. And then the biotech startups started happening about 15 years ago. We have some overlap in some of those companies, one of which we'll talk about. But maybe even before we get into some of the really exciting things going on in pharma, maybe we can just speak a little broadly about prevention. Because there really isn't, at least as I see it, a uniform consensus around how aggressively one should be trying to prevent ASCVD. Sometimes I feel like I'm in a position where I'm in a position where I'm in a position where I feel like people look at me as though I have multiple heads when I talk about taking steps towards prevention in 30-year-olds, for example. Because by any calculable metric, their 10-year risk is very low and would not necessarily justify the steps we might take. But you're more thoughtful, you're more astute when it comes to all these things. I'd like to hear your point of view and how you think about primary prevention, and we can differentiate that from secondary later on. It always is a hard sell to get a 30-year-old to start taking a statin, for example. And so I explain the primordial prevention concept, which is basically you want to stop plaque from forming before it's there. It's a lot easier to stop it from forming than it is to reversing it when it already exists. So we have this path, and right now, today, which is the mainstream, is that you wait until someone has significant plaque buildup or even a heart attack or a stroke. Then you treat super aggressively to get the LDL down. But we know from. Genomics, that if you have a low LDL throughout your whole lifetime, it prevents heart disease in a much greater degree. For example, I mean, if you lower LDL before you have a heart attack, it's very effective. If you have a heart attack and you lower LDL, it still has benefit. But once you have heart failure, there's no benefit to lowering LDL. And so the earlier you start, the better. What I like is the 8-gram rule, which is that 8 grams of cholesterol in your lifetime lead to heart disease. So that is. It's 200 milligrams per deciliter times 40 years is 8 grams, or 100 milligrams per deciliter times 80 years is 8 grams, or 80 milligrams per deciliter times 100 years is 8 grams. So you can think about it in that sense that the data says that if you keep your LDL below 80 throughout your lifetime, you don't get heart disease. So I think you said this as well. I mean, we have the knowledge to prevent heart disease now. It's applying it earlier in life that really makes the difference. That's my pitch to the 30-year-old. And there's a lot of pushback. And I try to then, if necessary, provide more information to them, which is we can do genetic testing, we can do polygenic risk scores. If they're old enough, we can do coronary calcium scanning or more advanced plaque analysis. We can look at other risk factors like LPLA or CRP, things like that, which give us more information about who's at higher risk. Of course, family history is so important. But believe it or not, I would think family history would be one of the most powerful motivators, but it's not always the case. It certainly was in you. I've shared my story about how rampant heart disease is in my family and how it was sort of my foray into even thinking about all of these cardiometabolic diseases. Your story, by the way, is just incredible in that it's identical to that of my father-in-law. My father-in-law's father, whenever my wife's grandfather also died at 47 in the hands of his 16. So my brother had bypassed at age 44. And then here's the story that why I'm so passionate about early is that, so I was 16, my brother was 14. My father died, my uncle, a family doctor, checked our lipids. They both were equally bad. So I then went on to start medical school. I took niacin in med school. As soon as statins became available, I started taking a statin. My brother, who's also a family doctor, went on and to become a vegetarian, really strict, diet, did not take statins until much later than at age 44, has a bypass surgery, a very significant coronary disease. It's an N of one, but it's pretty good comparison. You know, two brothers, one starts statin early, one starts statin later. And so that decade, the 30 to 40 decade, and even maybe 20 to 30, such an important timeframe when the plaque itself is starting to form relatively rapidly. And that's when you want to have your most effective treatment. There to prevent it. That's why I become an advocate for earlier in life, the better when it comes to the statin there. Now with women, we have to be careful about the whole pregnancy issue and stuff like that. And we also still balance that as well, but it's really upcoming that type of information. I know people bring up relative risk, absolute risk, 10 year risk. We're talking about more about preventing heart disease when you're 80 or 90, not 10 years from now. Yeah. I guess the other point that for me was a really wonderful way to think about, that I would credit to Alan Snyderman who wrote a paper. I feel like it was about 12 years ago. but he, at least for me, was the first time somebody repositioned the argument of rather than talk about treating five-year risk, 10-year risk, 15-year risk, or trying to stretch that out, reframe it as we treat causal drivers of disease. And if that's the case, then the discussion changes entirely. And people who listen to this podcast have probably heard me use the analogy, but it's why we target smoking cessation so aggressively. It's not that everyone who smokes gets cancer, and it's not that everyone who gets cancer smokes. Those states are true. It is that smoking is causally related to cancer. And therefore, the time to quit smoking is before you start. And if you've already started, the time to quit smoking is today, regardless of your risk going forward. So if a person has been smoking for one year, a pack a day, they have a one-pack-year history of smoking. That does not really increase your probability of getting cancer. You know, not until you hit 15 or 20 pack years that your risk really steps up. But there's not a single doctor on the planet that I would imagine saying, listen, Michael, I know you've been smoking a pack a day for a year. Keep it up for another 10 years, 15, 20 at the most, but then we're going to have to cut this out. Why? And that's an absurd example, but it gets to the point of causality. And so in as much as LDL is causally related to ASCVD, which you pointed out the Mendelian randomization, let alone the clinical trials, this would be one of the most assured parts of biology. It does become a little frustrating that it's not more widely understood that you have to treat a causal risk factor, regardless of the time horizon. And the analogy goes, it's very good. Smoke is a really good one, but also blood pressure, diabetes. We don't wait for stroke and heart failure to treat hypertension. We don't wait for blindness and kidney disease to treat diabetes. So I don't know why LDL gets this stepchild, type of role when it comes to how we manage, but it is causal and we know that. So why not treat it early as you can in life? And I think that's what we advocate for. We're not always successful, but I think we get the message across. And like I said, we have the tools now if we just apply them much more effectively. Why do you think that? I mean, not that we should waste too much time speculating, but I don't have a great answer for it. So I don't understand why we understand that nobody should be walking around with untreated hypertension. Even if they're young and even if they're asymptomatic, because most young people with hypertension would be asymptomatic. And you could argue, well, is the anti-LDL issue really all about drugs? Is it that people view it as sort of a pharma conspiracy or something like that? I mean, what is your take on why this one issue around LDL has become so contentious? Multiple reasons, but one actual reason I think is that people believe that LDL cholesterol can be totally manageable. I mean, if they ate one less egg or one less piece of meat or something like that, their LDL would come miraculously down to normal. And I think what we're learning from the genomic studies that we do a lot of genetic testing in the Lipid Clinic, we find that it's almost always a genetic factor involved. And so when people realize it is genetics, there's nothing they can do about it. They're already doing great lifestyle and so forth. That becomes, I think, part of the motivation to get them to do something. People don't like taking drugs. I get it. It is about the statin, but we try to find other ways to get the LDL down if necessary. But I wish there was more. Another problem we have, of course, is the primary prevention guidelines like American Heart are not very effective. They don't really emphasize as much as like you and I, if we were writing the guidelines, we'd have a very different approach to how we manage elevated LDL. We would be advocating a much earlier intervention in life. We just don't have those guidelines. That are there to help get physicians on board as well. It's interesting about the lifestyle point because, ironically, lifestyle has a far larger impact on managing high blood pressure, where weight loss and exercise individually and collectively have a greater impact on hypertension, which still means there are a lot of people out there, by the way, who don't respond, as you know, fully to those interventions and can be exercising of normal weight and still have essential hypertension and require medication. But I still don't see the reluctance or resistance to it the same way I do with managing dyslipidemia. So, I don't know. I don't have any great insight into it, but it does make me sad for people who become ultimate victims of it. I see the clinical ramifications of it. It is sad because it's preventable. We'll keep advocating. I think we're starting to see the trend happen. I mean, how many more trials do you need to show that LDL, no matter how you lower it, results in a clinical benefit? I think we'll talk about Obocytopenia. It might be the last mechanism once that study prevails, the PREVAIL trial. We have a 10th different mechanism of action of LDL lowering and benefit. And I think, hopefully, all the obstacles will go away and people say, "Let's just start treating LDL as early in life as feasible." Let's talk a little bit about Obocytopenia. Your colleague, John Kasterlin, was a guest on this podcast, gosh, I want to say three, maybe four years ago. Certainly one of the more enjoyable discussions I've had because I tend to really enjoy talking about these things. But I think it would be a fair assumption that many people listening to us now have either not heard that podcast, and if they did hear it, do not remember the ins and outs of CTEP inhibition. So let's assume that we're starting from scratch. Let's talk about this totally new class of drugs. Let's also just acknowledge as a disclosure, you are currently the CEO of a company called New Amsterdam Pharmaceuticals, which is the manufacturer of a particular drug we're going to talk about in this class. So take us back to, well, I don't know when the drug entered clinical trials, but I know when it ended, which would have been about 2006. I think it was '08. Okay. About Toreceptor PIV? Yeah. It could have been 2006. I feel like it was the fall of '06, but anyway. You're right. It was definitely Christmas, December, got the call, somewhere in that range, yeah. So it's- All right. So first, this was Pfizer combining this with a Torvastatin and a clinical trial. Okay. Go back from that a decade into the discovery of yet another mechanism, because you've already alluded to this, which is lowering LDL is the goal, but there are many paths to get there. Statins have taken one path, which is we're going to inhibit cholesterol synthesis. The liver will overcompensate by trying to pull more LDL into the liver, and that will lower LDL. I want to come back and talk about bile acid sequestrants. We probably won't get to ezetimibe. We might mention PCSK9 inhibitors. C-type inhibitors are totally different. So just explain what they do. It's good to start about what exactly CETP does. It's called cholesterol ester transfer protein. It transfers cholesterol from HDL into LDL. So when you block it, HDL goes up, LDL goes down. There's many other reasons. It also improves LDL clearance from the liver, like a statin does. We've proven that. It does help clear LDL as well. So animals that lack CETP, like the rat, the dog, they have very low LDLs, very high HDLs. They don't get atherosclerosis unless you give the rat or the mouse CETP transgenically. Then they get high LDL, low HDL, and they get atherosclerosis. Like the dog don't get atherosclerosis. They're carnivores. They don't have any CETP. Monkeys have CETP. Rabbits have CETP. Humans have CETP. We have, relatively speaking, high LDL, low HDL. So in effect, one of the most prominent atherosclerotic animal models is to give the mouse CETP, and that's what we use in a lot of our studies to show that you can induce atherosclerosis in a different therapy. You can reduce atherosclerosis. So it's very much a modulator of the LDL, HDL levels in mammals. Do you have a sense, given that everything you just described is a mammal, which means evolutionarily, while we look different today, we're coming from a very narrow part of the tree. Why do you think that difference exists, and is there a reason you can speculate on? It's conservatory. In other words, you didn't have chasing the woolly mammoth. You didn't have a lot of cholesterol. You didn't have a lot of cholesterol available to you in the diet. But why wouldn't dogs have the same issue then? They have plenty of meat. All they eat is meat and all that kind of stuff. They had plenty of cholesterol. So we think it was truly just a scarcity issue? Yeah, scarcity, I think. So animals that had more scarce nutrients would want to hyper-conserve cholesterol? Right, right, right. I mean, almost all, let's say, vegetarian animals don't have CETP. So if you look at it from that perspective, we're meant to be a vegetarian maybe. So how do you think how CETP plays a role in lipid homeostasis? But it's a conservatory mechanism. If you can't get a lot of cholesterol available from the diet, it's just a way of conserving cholesterol in the body. So when you block CETP, you lower LDL, you raise HDL. You actually funnel more cholesterol into the intestines. So you lose a lot of cholesterol in your body by blocking CETP. So the story was, it was all about HDL raising. At the time, this is 20 years ago, HDL raising was the holy grail. We had data from the Framingham Heart Study that if your HDL was high, you're protected from heart disease. They used the ratio total cholesterol divided by HDL. That was a real famous ratio that we looked at. A lot of doctors still look at that as a risk predictor. Raising HDL, we had a couple studies, the Helsinki Heart Study, the VA HIT trial using a fibrate, lowered HDL, raised HDL a little bit, and it had some heart disease benefit. And so everyone's been trying to figure out what's going on with HDL. And where were we in our knowledge of Niacin's impact on HDL and events? niacin alone in the coronary drug project did lower events. We also knew niacin as one of the drugs that was studied and had alone, that was the pre-statin era, had a reduction in cardiovascular events. In secondary prevention? Secondary prevention, yes. How significant relative to what we see with statins? It was modest, not nearly the same as statins. Obviously, niacin has a lot of side effects. I took niacin before statins because that's what we had. You get flushing and GI side effects and liver issues and stuff like that. But no, we had niacin. And niacin also raised HDL cholesterol, didn't it? Quite a bit, like 20, 30. That was the best. That was also studied. It didn't work out on outcomes on top of statins. It was two studies, Aim High and HPS Thrive trial. Both showed niacin on top of statins did not lower LDL, did not lower events. The Thrive HPS2 trial there was, it looked like, if you looked at it, in another way to look at the analysis, it did lower events by LDL lowering, because it lowers LDL also. That was actually post-tricetrapib. So tricetrapib was the Pfizer CTP inhibitor. Everyone was rushing to get a CTP inhibitor because it raised HDL 50%, 75%. We thought we'd have the cure for heart disease. Every 1% increase in HDL in these other trials lowered risk by 3%. So you can see the magnitude of the benefit would be quite substantive if you can raise HDL. I personally had a low HDL in my family. So it was like, actually, I was the first one to patent CTP inhibition back in the 90s. I was the first one to file a patent on CTP inhibition. 1993 was the patent was issued. I had a lot of hope that CTP inhibition would be the end of heart disease. So tricetrapib was underway. They rushed it, even though they knew, and I was involved in the first phase two trial, that it raised blood pressure quite a bit. It wasn't clear how much, but we knew it raised blood pressure three points, five points maybe. So it went. It went into the big trials. And unfortunately, it was stopped due to increased mortality, both cardiovascular and non-cardiovascular mortality. So it was a real big disappointment. And do you think that that was attributed solely to the increase in blood pressure? The blood pressure increase actually was only the tip of the iceberg. The drug had a very prominent effect on increasing, getting to the adrenal glands, and would markedly increase aldosterone and steroid production. And so it was, just an off-target effect. We know that because in animal model, like the rat, they would give tricetrapib and the blood pressure would go up dramatically within an hour without, and there's no, they have no CTP. The rat has no CTP. So that said, it's not, it's an off-target effect. And since then, there's been a lot of CTP inhibitors that have, let's say four. Yeah. So let's take them in order though, because the story is so interesting. So this was a big blow to Pfizer. I don't remember. So I'm curious how it felt from the inside. Was that viewed as a shot across the bow that this target might be the wrong target or was it, no, we realized immediately this was an off-target effect. It was just a bad drug. Merck was next, correct? No, Roche, Dalsetrapib. It was mostly off-target. That was, obviously there were some that thought, okay, maybe the target's off, but that came later. More validation of the target actually came later as well, that it is a valid target. I can get into that. But the initial thinking was it could be, well, an off-target effect. And Pfizer did a lot of work on understanding, that others that followed can actually isolate the off-target effect to a certain composition in the molecule itself. I mean, they knew that the chain around Torsetrapib, that was the inducer of the aldosterone secretion. You can do that in cell models. You can find what was the component that raised the aldosterone. And they developed other CTP inhibitors that lack that component of the molecule. And so those were the next ones to follow. And then again, it's all about HDL. Keep in mind, it's all about HDL raising. No one's thinking, about it for LDL lowering. That's a key thing. What was the thinking, Michael? So aside from the fact that epidemiologically, we could observe that people with high HDL, low triglycerides and low LDL did better. Was there any sense of mechanistically, why would raising HDL do something? In other words, how was causality established as opposed to association? It was a great question, but there's a lot of work that went into the HDL, function. What does HDL do? So HDL is a lipoprotein that is also made by the liver and the intestines. And it goes to different organs and it basically picks up cholesterol. It's effluxes cholesterol into the lipoprotein. It goes from an empty garbage truck to a loaded garbage truck, an empty pita pocket to a spherical, how you want to describe it. It matures. It goes from this pancake up to a big ball filled up with food. And it's a very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, very, and there's different enzymes along the way that kind of help maturate the particle. And once the spherical particle is mature, it goes to the liver and gets cleared. And actually, the predominant route, most people don't realize this, but the majority of bile that the liver makes comes from HDL. It comes from HDL. That's the bile. It goes funnel more into the biliary system and then out into the intestines. So HDL is the precursor, but it has a lot of functions that are really interesting. It picks up a lot of garbage. Along the way, it picks up all these inflammatory components, the cytokines, and it's like a dump truck. It's picking up stuff and it takes it back to the liver for clearance. That's what the purpose of it is. And part of that is cholesterol. And so people thought it's going to the plaque. It's picking up cholesterol. We call it reverse cholesterol transport. And it picks up the cholesterol and removes it from the plaque. And that's why you get less heart disease with HDL. So it was all mechanistically based on that finding. Even though the amount of cholesterol that it got from the plaque was actually minuscule compared to what it does to other organs. But it's the vehicle for cholesterol transport. And it also has other functions. It's very important in immune function and trying to battle innate pathogens and things like that. It has a lot of other important roles to play in human health. But that was the reason why we thought HDL being high was good. And then it functioned by removing cholesterol from the artery wall and taking it back to the liver for clearance. Learned it's a lot more complicated than that. But that was our thinking back in 2006 when Tercetrapib unfortunately kind of failed. And just to be honest where I was, I mean, I was a big fan of Tercetrapib even though the blood pressure went up because the HDL raising, the magnitude of that benefit would be greater than a three-point increase in blood. So I was thinking, okay, if it raises blood pressure a little bit, it raised HDL 75%, we should get a net benefit. But it turns out it was much more. It was much more complicated than that as far as the side effect profile. Yeah. How much did HDL go up with Tercetrapib? About 75%. Wow. So despite that, that really tells you the off-target effects were devastating. Right. Yes. Did it have an effect on LDL very much? I don't remember. About 15%. At most, maybe 10% to 15%. It was really not even something people even paid attention to, the LDL effect. Okay. So then the Roche compound comes along. What was the story with that trial? So it's a weak CTP inhibitor. And they even called it a CT modulator, a very safe drug. And it raised HDL 30%, maybe 40% in some trials. So not much weaker HDL raising effect, no LDL effect. So it went into a large outcome study, very safe, no issues. It reduced the risk of diabetes, which we'll come to later. That was one of the things about the HDL raising benefit that we can talk about. It reduced the risk of diabetes benefit. Major adverse cardiac events. Right, right. Heart attack or stroke reduction was nothing. There was no benefit there. Not even a trend. It was just completely flat, but very safe. And so that was the second failure, high-profile failure. Actually went to another trial later. It's still neutral. No benefit on major adverse cardiac events. That's number two. And then Merck? Then Lilly. Oh my gosh. Okay. Then Lilly, which was evacetrapib. That one's a good molecule. Again, very safe. And was studied. Again, it was a time when Lilly did not have the resources it has now, obviously. And so they were trying to go fast. Everyone's trying to go fast because again, this could be a huge opportunity to reduce heart disease. So it was all about age. So they went into a study with acute coronary syndrome primarily. And they showed, again, LDL lowering about 15% to 20%. HDL raising, again, 75% or so. A very good HDL raising effect. They only went two years, though, post starting the trial. And they stopped for futility for no benefit on major adverse cardiac events. Secondary prevention. It was a high-risk secondary prevention. By the way, Michael, the first two studies were primary or secondary? All secondary. These are all secondary prevention. Yeah. What's important about that trial is azetamide, which is now a well-known, we use azetamide all the time, Zetia, for lowering LDL. They also did an ACF, acute coronary syndrome trial, which was similar to what was done in the ACCELERATE trial, which is the Lilly trial. We know that two years is too short because in a similar trial with azetamide, which is a well-proven LDL lowering drug, it has, everyone recognizes the benefit of azetamide. It took more than two years for the lines to separate. After two years, their lines were, there's no difference in major adverse cardiac event. But after two years, they separated. And so the similar would have happened, we believe, with evacetropib and the ACCELERATE. Although with Repatha and Pralulin, we did see benefit at about two years. This was only a 15% LDL lowering. Yeah, yeah, yeah. So it's also interesting, in the Odyssey outcome study, which is the praline, which is the other PCSK inhibitor, if you look at populations that had LDLs below 100, which is what this, they also didn't separate until after two years. Same with Fourier? Which one was more heavily? No, Fourier was for patho. But which one was more heavily statinized? I can't remember. They both are pretty, but Fourier was not a Q-coronary syndrome population. Got it. It was a chronic stable. They sent a separate, Q-coronary syndrome populations sometimes can be pretty sick and they get a lot of events. And so you have to go longer to see the benefit. Are you saying that your view is maybe the Lilly study was stopped too soon? It was stopped for futility when it should have kept going. That was for us a big issue for our drug, Obacetrapib. That was the hardest one to explain. And what were the features of the Lilly drug in terms of HDL? LDL-C and LDL-C kinetics. Lordelli about 15 to 20%. And raised HDL-C. HDL again, 75% or so. It's a good, but the thing is it was safe. It actually had a total mortality benefit that was significant, that it was not a major adverse cardiac event benefit. So the drug would never have been, but that was not the primary endpoint. That's interesting. It had an overall all-cause mortality benefit. Right. What other causes was that attributed to? Well, it was largely cardiovascular, but it has some non-cardiovascular mortality. But cardiovascular mortality was almost significant. There was also some non-cardiovascular benefit as well. Did they pre-specify that they had to have an outcome at two years? Is that why they stopped it? They had pre-specified that there would be an analysis at two years. There were also corporate issues involved. It was a tough time for Lilly financially. It's very different than where they are today. They had to make some quick decisions about prioritizing their pipeline. As big corporations go, you have to make these decisions. So they had decided to cut the study short. Again, HDL raising. You would think we'd have a benefit already. So it was the LDL lowering wasn't really thought of as the main mechanism there. Did that study show any improvement in diabetes? It did also, yes. All the CT inhibitors, even torcetrapib, showed a diabetes benefit. All of them. So this is, again, why we're focusing on that with ovacetrapib as well. So the important study that was the Merck study, that actually saved the class, even though the drug itself didn't make it to market for different reasons. It was to Merck's credit. I mean, they started. The trial, again, all about HDL. But when they saw what happened with the Lilly drug and dalsetrapib, they wanted then to make sure the study was adequately powered to maybe pick up an LDL benefit. They had 30,000 patients. That's perhaps the largest outcome study ever done. And they went for four years. So a very large study. They went for four years. The baseline LDL was 60. So we're talking about already low LDL. They got a 17%. LDL lowering 11 milligrams per deciliter. Absolute LDL lowering. And they got a 9% relative risk reduction, which is what you'd expect, if not more so than what you'd expect. And so it proved the LDL lowering benefit with CT inhibition can translate into a cardiovascular benefit. And that was the key study for us. Now, the reason why the drug didn't go forward was it had this unfortunate deposition in fat tissue that wouldn't stop depositing. So if you took it, you would not wash the drug out for years, actually. So there's also environmental issues. It gets in the water supply. There was just a lot of issues that Merck would have to deal with with a drug with that type of pharmacokinetic profile. And how did they figure that out only in the large phase three study without knowing it in, say, a phase two? Like, what was it that even brought that to their attention? As the studies went along and they started getting more in the phase two studies, they didn't look at long-term clearance of the drug. They didn't do the PKs? They did the PK. They knew it was a long half-life. They didn't realize how long. They didn't realize how much it got deposited. I did some of them. I actually did fat biopsies to see how much drug was in the fat tissue. And this was an oral drug? Oral drug. Lipophilic, yes. Wow. Yeah. So it was unfortunate in that it was just not a viable commercial drug for that reason. Even though it had good safety profile, it lowered MACE. But also because the magnitude of the MACE benefit was modest, people don't realize. It's an issue for how you market the drug, but from a proof of concept of proving the drug works to lower LDL and reduce events, it was a great study to confirm that the LDL lowering with the C-team inhibitor can, in fact, result in a cardiovascular benefit. You've referred to this a couple of times, so I just want to make sure people understand why this is the case. And it actually goes back to sort of our argument earlier about causality. When you line up all of the primary prevention trials, full-circuit. Full stop. All of the secondary prevention trials, full stop. All of the Mendelian randomizations and all of the epidemiology, and you plot on the X-axis LDL-C and on the Y-axis event rate, they're all a bunch of lines going down. Right, right, right. So they're four distinct lines, different slopes based on different. And therefore, given how tight those regressions are, it becomes very easy to predict what you're getting at. I just want to make sure the listener. understands why it is that you're saying if you have a 17% reduction in LDL-C from 60 to 49, you would expect an event reduction on a relative basis of 9%, et cetera. Yeah. The formula is easy. It's well-established. For a one millimole, which is 38.8 milligrams per deciliter of LDL, you get a 22% relative risk reduction. And that's largely linear. It's linear, right. But it's absolute is the key. Absolutely. Absolutely. It's not percent. You've got to look at the absolute LDL lowering, and then you can calculate the benefit. And we're doing that for, obviously, our outcome study. We can have a predicted benefit based on our absolute LDL lowering that we hope to achieve in our prevailed trial. You can power studies accordingly. You can see what the benefit is. As long as you go long enough, too. That was the other key thing. In the first year of treatment, you get half the benefit at best. It takes time for the lines to separate. And that's what gets back to the other point you made earlier, which is all of these regressions. The regressions are independent of how you do it. The Mendelian randomization says we're going to lower it genetically. It's the genetic lottery that determined your LDL versus mine. The primary and secondary prevention trials are based on a potpourri of drugs. Same with the epidemiologic stuff, which combines both genetic and drugs. So, again, it speaks to this idea that reinforces the causality of LDL. Because independent of how it's lowered, you're getting the same effects. You'll often hear people say things like, well, it's hard to deny that these drugs improve outcomes, but it must be something different than LDL lowering if you want to deny that LDL plays a role. They'll talk about pleiotrophic effects of these drugs or things like that. But obviously those arguments become a little bit silly when you consider the totality of the evidence. Right, right. I've never been a pleiotropic. In fact, I was the one who always debated that issue. I've always been, it's LDL, it's LDL. Now, I think the argument is stronger that there's nothing special about statins other than they're very effective and well-treated. But there's nothing special about the LDL lowering about statins that result in a greater benefit than any other LDL lowering drug that can achieve the same levels in a patient. So, with all of that as background, now let's talk about Obacetrapib, the work that you and John and the team, of course, but let's just talk about how you decided it was worth going after this for a fifth time. Right. I had sold my previous company an interleukin-6 antibody for heart disease, inflammatory. I don't know if you remember IL-6, but it's the key inflammatory cytokine. And that study is actually coming out this year. It's called the ZEUS trial. It's a big, big study coming out. I had sold Corvidia and John said, let's get Obacetrapib back from Amgen. Amgen had put it on the shelf because Repatha had struggled on its launch. They deprioritized it. So, they kind of had it sitting there ready to go into phase two, maybe even right into phase three, potentially. So, we teamed up together and started, New Amsterdam Pharma. How many years ago was this? This is five, almost, this is our sixth year now. That's so interesting because Repatha launches in 2015. Right. They kept Obie on the shelf for five years? I think they bought it in 2017. They bought it in 2017. Interesting. They did actually did a lot of great work on the manufacturing, the process. They worked on the, made it much more cost-effective manufacture, but they didn't do any clinical trials. They just kept it on the shelf. It already. We had an IND in the U.S. or this was all. Yeah, we had phase two data. In the U.S.? In the U.S., yeah. Okay. It was ready to go. So, we initially thought about, you know, statin intolerance and using it for those patients as a quick route to the market, but we realized the FDA view on CD inhibition because of the history, we really didn't have a path there. The FDA does not like statin intolerance as an indication. They're very wary of it even really being a true thing, but believe it or not. I mean, you and I see it. I don't know if we all. See it, but. Sure. In the academic world and in the FDA, they don't really believe it as a true phenomenon. Because when you look at the placebo-controlled trials, it's, you know, very low rates. It's about 4.9%. Yeah, but even true statin intolerance is very hard to find. I mean, it's in the trials. But anyway, it exists. It exists. That was our first path. However, once we met with the FDA and realized we need to go into a full boat LDL lowering path, which is a much more larger program, and also we know we had it at a very early time, outcome study at the time of the launch of the drug because of the history. But what were the phase two data that you had at the time of acquisition? We had the TULIP study, which was the set of John and Led. in a predecessor company. Yeah. Can you remind me and the listeners what that study looked at? So it showed that 45% LDL lowering. Okay. So what was different about OB? It's a much more potent. So it's only, the other CT inhibitors are all in the 100 milligram plus range and they lowered LDL, as I mentioned. And you're at 10 milligrams. You're at 10 milligrams, even five milligrams we had initially too, lowered LDL on that 40 to 45 to 50% range in the trials. And the HDL raising? 150%. So it's a lot more effective on both lowering LDL and raising HDL. It was just a much more potent CETP inhibitor. And the duration of the TULIP study was how long? It was just a short-term study. I think it was eight to 12 weeks, something like that. It was a relatively short study. It was very effective, very well tolerated. It was a really nice LDL benefit. So we wanted to look at for LDL lowering. Again, in the meantime, all the Mendelian randomization studies, besides the Merck data, at the same time, or roughly the same time, all the Mendelian randomization studies confirmed that LDL lowering translates into cardiovascular benefit. Weren't these the same studies, sorry to interrupt, Michael, that suggested that the HDL raising had nothing to do with the benefit of CETP inhibition? Right, exactly. And other HDL raising genes saw no benefit. At least the benefit could not be explained by the HDL effects. If you looked at HDL raising genes that are associated with lower risk, they also had other things like LDL lowering or triglyceride lowering, there was no pure HDL raising gene that was associated with protection. This was a paper in Nature circa, what, 2012-ish? Yeah, right, exactly. Yeah, 10, 15 years ago. So that was the other important. I feel like that doesn't get enough attention. To your point, you said, look, there are still a lot of doctors out there, a lot of patients I hear saying, well, I hate the term, I hate the term, but people know what I mean when I say this. My good cholesterol is high, so I'm okay. So notwithstanding the nomenclature flub, even if they were to say my HDL cholesterol is high, I'm okay, the answer is no. We've known for over 10 years that that is not true. So you notice I really worked hard to avoid saying the term good cholesterol. I'm avoiding using that term because our mutual friend hates it, as we know, but it's the wrong way to phrase it. It's the wrong way to phrase it. But again, I think it's one thing to hear patients say that and they can be forgiven because they don't live in this world. But I really struggle when I hear physicians say, yeah, but his HDL. Cholesterol is high, so we're okay. I have a patient that comes to me and their LDL-C is through the roof and their HDL-C is high. And they say, well, yeah, but my doctor told me that because my HDL cholesterol is so high and my triglycerides are low, I'm fine, right? So HDL is really interesting. We believe it could still have some cardiovascular benefits if you raise it the right way. And also, because HDLs, there are definitely genetic factors that raise HDL that increase risk, like SRB1, for example, that's a known HDL gene that does increase risk. We know alcohol raises HDL and causes all kinds of higher mortality issues. So when you look at HDL, it's a complicated thing to have a high HDL. You really need to. We could talk about a whole podcast about how we evaluate a high HDL patient and how we think about how to advise them about what it means, because sometimes it could be quite good. I have a friend with very high HDL cholesterol, about 100 milligrams per deciliter, and modest LDL cholesterol, so maybe also 100. 110 milligrams per deciliter. And he had always assumed he was totally risk-free. Maybe his LDL was even lower than that. It might've been 90 to 100 with HDLC of 100, 110. And I was able to convince him. I said, you know, look, you're right. Statistically speaking, your HDL cholesterol is probably reflective of something good or protective, but I've read enough cases in the literature to see that we could be looking at highly dysfunctional HDLC. So would you mind giving a CT angiogram, which he did, and he had significant burden of disease? Yeah. So he probably has the SRB1. That's Ashkenazi Jewish predominantly. It's where we find it most commonly. It's still relatively rare. We see, I have a series on that in my Olympic clinic that have the high HDL due to SRB1. There's NLT lipase. There's like three HDL-raising genes that either don't protect or increase risk. And then you have alcohol. So you throw that in the mix, you get a very complicated story about HDL being high, being protective. The reasons to believe, we still have hope that Obocytopib's HDL-raising benefit can result in a cardiovascular benefit, but we're also focusing primarily on what the other HDL benefits could be, like we're still talking about later, like diabetes prevention and Alzheimer's. That's what we hope is linked to the HDL-raising benefit. We're investigating that now in all our studies. So when John was on the podcast, again, I think it was four years ago-ish, but a lot has happened since then. So let's talk about where we are today. What is the state of understanding of Obocytopib? And let's start with cardiovascular, because what John predicted at the time was this is going to have benefits in cardiovascular disease, but it's going to have benefits in metabolic disease. It's going to have benefits in Alzheimer's disease. So let's take them in that order. So let's start with what is known today based on the ROSE trial is the most recent. Well, no, Broadway- Broadway's the most recent. Tandem, yeah. So we've now done two more phase two trials, and three very large phase three trials. And they're all been completed and were actually filed in Europe for approval. And the US were waiting to time it on the outcome study called. So we started Prevail. So we had, I hope, the courage and the foresight to start our outcome study at the same time as our phase three trials. As a small company, we're able to, knock on wood, even though we'd have the money, to finish the trials, start the trials, get them completed, and then we raise money along the way. Now we have plenty of cash to finish the Prevail trial. So we feel it really worked out well for us because the success of the phase three trials allowed us to fund the finishing the other trial. So it timed it extremely well for our efforts. We had ROSE and ROSE2. Both showed, again, the 45% to 50% monotherapy benefit. And then in combination with the Zetamide, you know, in that 55% range, higher, better LDL lowering. We then did what's called Brooklyn, which is a familial hypercholesterolemia trial. I know you've done multiple podcasts on- It's an autosomal dominant genetic disorder, very high LDL, showed a 40% LDL lowering over a year. So it's a one-year study. Tell me about those patients. They were already on- Almost all were on high intensity stans. Many were on Zetamide or PCSK9 inhibitors already. These were very well treated, but their LDLs were still too high. How high? Well, the average LDL is roughly around 100, something like that. So in other words, the inclusion criteria is not limited to exactly which drug you're on. It's just that you're on maximum therapy, and your LDL is still above a certain threshold. Right, right. So on the familial hypercholesterolemia patients, when you show up at a LDL-C of 100 on whatever combination you're on, Obacetrapib lowered it by an additional 40%. 40%, 40%. So lowered it from 100 to 60 milligrams per deciliter on average. Approximately. That was, I think, those are approximate numbers. About 40% was the reduction at the end of 12 months versus placebo. And then the Broadway trial was, these are all atherosclerotic cardiovascular disease patients. Again, all on maximal statins, majority on high-intensity statins, like 70% were on 20 or 40 of rosuvastatin or 40 or 80 of atorvastatin. They're all very well treated. And we got roughly around a 35% LDL lowering benefit, and then adjusting for placebo a little less than that. But it was around that percent change at 12 weeks, and then it continued for 52 weeks. And so that was our two pivotal phase three trials. And then in combination, with ezetimibe, we did another trial called Tandem, where the LDL lowering was very much 50%. So we have a combo pill. We're developing the two drugs together. What was important about Broadway, though, that really helped us a lot was we showed in that study a 21% reduction in major adverse cardiac events at one year. It was not specifically significant because this is 2,500 patients, but it was the right direction, and it was pretty powerful. If you look at kind of a landmark analysis, we, we divide, take the first six months away, it starts to become significant. And then remember, it takes time for these curves to separate. Everyone got excited. Again, we're trying to obviously leverage that with Prevail, because it's almost identical population in Prevail, which is 9,500 patients. And it's an ASCVD, atherosclerotic cardiovascular disease population. LDL, again, in the higher end, that's the key. You have to try to get higher LDL levels, but not being too high, where it becomes, you get too much drop into therapies, or you get an ASCVD on ethical issues. So these are all on maximally tolerated stands. That's called Prevail, and that study now is approaching, we're in the year three of the study now. And this study will read out when? We have two factors that stop the trial. One is that we have a minimum follow-up of two and a half years. Again, the learnings from the, from the other trials. And the other is also event-driven. How many events depower the study appropriately for, for what we call four-point MACE, which is the heart attack, stroke, cardiovascular, coronary death, and then revascularization, coronary. So those are the four-point MACE. So we have that. Events need to be adequate to stop the trial. So that may take us into a little bit longer than the two and a half year. The two and a half year mark ends this year, at the end of this year, for the minimum follow-up. That will be a trial evaluated in both Europe and the United States? It's all over the world, yeah. China, Japan, everywhere. It's 400 plus sites, and it's a global study. And the outcome of that study, should it be positive would be approval in Europe and North America for Obesetrapib in secondary prevention? We actually don't need it for approval in Europe. Why is that? Well, it's a different system. They believe in LDL lowering is LDL lowering. So you don't need- They don't need the outcome trial. They don't need the outcome study for approval. The US is different story. Then they have a year to set up their payer mix. So they have the year for the outcome study to kind of come into the payer reimbursement. For US, it's different because you want to line up your reimbursement at launch. And so we want to have the outcome study when we launch. So actually Europe will be first. I went through the ROSE-2 trial the other day. And one of the things that I found interesting was, and we'll link to the study so folks can see it, but the LDL-C lowering, there was also an NMR for LDL-P lowering, and then there was ApoB, and there was quite a discordance between those. The ApoB lowering, I don't remember, was maybe 16%, but it was much more modest than the others. What do you think accounts for that? It's something we're looking at. I know a lot of our good friends Tom, Alan, they're all ApoB. I'm more of an LDL-P person for a couple of reasons. One, it's easier to get in our lab. Really? Yeah, easier actually. ApoB is still pretty easy, but- I mean, I feel like ApoB is the easiest thing to order. Yeah, but LDL-P, but also LDL-P to me is more commonly discordant than ApoB. You can see it more easily because ApoB, LDL is 80, ApoB comes back 85. Is that really- That kind of thing. Usually would typically have with LDL-P of LDL-70, LDL particles 1500. It's very easy to see the discordance a lot easier. Which assay did you use for NMR? This was the- This is the liposcience. Liposcience one, which is owned by LabCorp now? It's owned by LabCorp, yes. This is Jim Cromwell's old assay from- Right, right. Actually, no, we use the liposcience, yes. That was the assay that we used. Okay, so that is the most reliable one to my knowledge. Right, exactly, right. And so we're doing a lot of work confirming that Tom actually published a paper, when LDL-P and ApoB are discordant, what is driving that? Which is not very common, but you do see it. And it's insulin resistance and a lot of small particles, you get discordancy in ApoB and LDL-P. And then there's a study done at the- Sorry, you said ApoB and LDL-P. Did you mean ApoB and LDL-C? No, LDL-P when they're discordant. In other words, when ApoB is not high and LDL-P is high, what explains that? What is the reason why you have a normal ApoB and a very- Very high LDL-P. But I don't understand why small particles would explain that discordance because each particle still has one ApoB on it. It turns out the mass of ApoB is different by the size, slightly different from each particle. And that we believe is the explanation. Why is that? It's because when you have the smaller surface, the mass is not just the protein, there's also other sugar molecules that attach to that that make the mass of, when you measure them, so ApoB is a mass assay, the LDL-P is the NMR, the nuclear magnet, the resonance. So CTP inhibition is the one example where you get different results. LDL-P goes down very much dramatically. Small particles go down by 90%. You wipe out small particles. ApoB doesn't go down as much as you'd expect. And so we're trying to understand that better. Actually, we're doing a lot of work on the UK biobank, trying to see when that happens, where does risk follow? That's actually going to be very interesting when you get your outcome data. Assuming, that the discordance continues between those two biomarkers, because you'll be able to go back and say, well, we would predict based on this LDL-C or LDL-P lowering what the event reduction should have been. But that might be different than what's predicted by the ApoB reduction. People have brought that up as an issue, but John and I both feel very confident that it's going to be as good. One thing I think that we look at, it was called non-HDL cholesterol, which is very close to ApoB. It's LDL plus VLDL cholesterol. We go back to the Merck trial, the Reveal trial, that showed the benefit there was driven, it was really highly correlated with non-HDL cholesterol, more so than ApoB. Although there was that paper in either JAMA or New England Journal of Medicine about six years ago that compared ApoB to non-HDL-C and ApoB performed better. Others have shown the opposite though. It goes both ways. Listen, I love ApoB, I always have, like LDL. It's important to understand what discordance means. You can get discordance with using non-HDL, ApoB, or LDL-P. I think by and large they tell you the same thing, by and large. Yeah, this is a third order term. Yeah, yeah. The cheap way is non-HDL. Then ApoB and LDL-P are a little bit more precise, but another blab test involved. We know that in our ApoB lowering with Prevail, we still do okay. We do okay with the outcome benefit that we want to achieve. We even do better if we use non-HDL. But of course, what Obesetra-Pib has that we're also excited about is the LPLay lowering benefit. How much was that? It's about 50%. Which is more than a PCSK9 inhibitor. Right, right. In the 50 to 150 range, you have to bracket it by the range of LPLay. What do you think explains that mechanism of action? We don't know for sure because we've been trying again. We don't know why PCSK9 lower LPLay. We don't know all the reasons why those drugs lower LPLay about 15% to 20%. But we were looking into this. We have done a clearance study. It does reduce production of LPLay. We've done an actual assay looking at this study labeling LPLay and seeing that it does reduce synthesis in that study. It was a small study, so we want to try it. But we don't necessarily have all the reasons. But LPLay lowering with the other CTV inhibitors as well, but not nearly as much. It was the same thing. We have a much more potent CTV inhibitor. And where are we right now with the antisense oligonucleotide that lowers LPLay? That is still in a phase three trial? Yeah, it's coming out this year. It's called Horizon. It's a really important study. Although it was extended. It could have been stopped for futility, right? It could have been stopped for futility. And it has a lower than expected event rate, which probably brings us to another important discussion about how do you treat a high LPLay today? What is the mechanism? So you want to bring the LDL down. So they brought the LDL down to 60 in Horizon. And so they had a lower event rate than expected. And so I think that proves what we're doing today. I'm sure you hear it too. But when you have a patient who has high LPLay, they go, "I don't want to be on a high LPLay." They're like, "I don't want to be on a high LPLay." They're like, "I don't want to stand because it raises LPLay." And so what do we do? Well, the truth of the matter is you bring the LDL down, you really mitigate risk substantially. So you think that the issue with that study was their LDLC was so low that you didn't get enough events. So abolishing LPLay with the drug, the ASO, didn't matter? No, no. I think it will matter. Well, it didn't matter in the timeframe that they looked. Didn't need to collect enough events. I mean, it could well matter. I mean, it's going to come out we believe sometime this year has been reported. So that'll hopefully convert the LPLay to our very opening discussion about causality. That becomes then, we know it's an important risk marker. We believe it's causal. A lot of reasons to believe it's causal. And now we have a study that proves that lowering it has benefit. It'll be a great achievement. Now, this may not be the best LPLay lowering therapy by far. I mean, there's others that look a lot better that are moving into big trials as well. And so it's the LPLay era is getting started. I mean, we're getting to another, hopefully very important causal factor that can be treated aggressively with therapy. And we hope Obacetrapib can be part of that treatment paradigm. From a purely cardiovascular standpoint, how do you see Obacetrapib being used? Should the outcome trial end in the fashion that you would expect? Where do you think it fits into the current toolkit we have with respect to pharmacologically lowering LDL? I want to say, again, your question is the right one. It's the right way to frame it. We have to have a positive prevail trial, and we have to show the benefits of the drug on top of statins. However, when you think about what statins do well and what they don't do so well. So statins lower LDL, and they're well-tolerated, and they reduce cardiovascular events, and they're generic, and they're very easy to prescribe. That's all the good things. What does statins not do so well? It raises the risk of diabetes slightly. It raises the LPLay, and it does not lower small particles very well. It lowers mostly the non-small particles. But does Obacetrapib do well? It lowers the risk of diabetes based on our Broadway trial data, as well as other CTV inhibitors. It lowers LPLay in that 50% range, in that moderate band, and it lowers the risk of diabetes, lowers LPLay, and it lowers the small particles by 90%. And so it would be a great companion drug to statins. We believe it becomes the go-to drug after statins for those reasons. It makes the statin liability much easier, but the statin liability issues mostly go away, and it really is a good companion drug to a statin for that reason. Now, we have the Acombo pill with the Zetamide, which puts us in the same range as the PCSK9 inhibitors or even the upcoming oral PCSK9 inhibitor. There is another issue, John, with statins that I don't think gets enough attention, because I realize it hasn't demonstrated a clinical harm, but there's something that always, I guess, we just, out of an abundance of caution, pay attention to it, which is it can have a negative effect on your health. It can have a negative effect on your health. It can have a pretty significant impact on transaminases, especially when combined with the Zetamide. And we see that. Honestly, I think we see that far more than it's reported in the literature. So I understand what the guidance says. The guidance says if the AST and the ALT rise by less than 3X, you can ignore it. It's not clinically significant. But that means you're going to be tolerating patients on Crestor and Zetia walking around with AST and ALT of 80. Right, right. And the reality of it is I just have a hard time believing that that makes sense. What's your view on that? Do you think I'm being too much of a Puritan? - Not really, I kind of feel the same way. I'm a first do no harm kind of guy. I mean, you bring up a very big point for me in my clinical practices. I don't like high dose statins. I don't like 80 milligrams of atorvastatin in particular. I don't like 40 milligrams of rosuvastatin. Have you seen Tom Dayspring put out a beautiful figure? It's one of like your classic Tom figures that he pulled out of all the literature. And it shows the dose response of every statin. And we now show it to our patients, especially those that come in on high dose statins. And I'm sure it demonstrates exactly what you're about to say, which is you're getting virtually all the bang for your buck at that lowest dose. And that curve is so concave down that it's almost unjustifiable to be on a statin above 50% of its max dose. Yeah. I mean, it's like the number needed to harm versus the number needed to treat benefit is just not desirable. I try to cut the statin. Patients, by the way, they don't want high dose statins either. The whole high dose statin guideline paradigm is off. It doesn't work. And in defense of it, look, I want to be charitable to everybody. It made sense 25 years ago. Because 25 years ago, you didn't have rapatha. You didn't have praluent. You didn't have ezetimibe. You didn't have bampidoic acid. You had nothing. This was your drug. We didn't have evidence of benefit either on top of these drugs. Now we have many studies showing the benefits. The tide is turning. People are now advocating guideline. Europe is already on board with more combo therapy early just to get combo therapy. So I think Obacetrapid then becomes, in my view, based on our data, should become the next go-to drug. And if you need even more potent, you can add the ezetimibe combo pill. So we believe that with OB alone and OB with ezetimibe, 90% of patients are done with their lipid treatment. And so that's how we think. For primary care doctors, that's what they're looking for. They're looking for something they can just add to a statin and then they can call it a day. Explain something to me. So if you go and buy branded Zetia. Today, it's not that expensive. If you go and buy branded Nexlatol, I mean, it's as expensive as an injectable monoclonal antibody. So do you, and maybe you don't want to talk about this, but I have to ask, I mean, when you think about how Obacetrapid will be priced in the United States, is it going to be priced more like Zetia or is it going to be priced more like Nexlatol? Unfortunately, it's all about access, not about price. That's the big difference. So we haven't decided on pricing. You don't do that until you launch, but it's really fortunately how the system works. If you price too low, the PBMs don't have any rebating profits to make, so they don't put it on a formulary. And so you got to be able to play the rebate game and price it accordingly. We're starting to see that breakdown also with Lilly Direct and all these. We love to see that system get better as time goes on. And so people can just pay a reasonable price out of pocket. They can pay a reasonable price out of pocket if they want to, and they get the drug. Look, you don't need advice from a bonehead with a podcast, but I have to tell you, I really think it is a terrible mistake when these drugs are priced outrageously. Well, we know C-Boropatha was a huge example, right? Yeah. I mean, what a blunder to price that drug at $16,000 per year. I mean, they could have run roughshod over the market if they had just priced it within, yeah. So again, assuming that the results of Prevail are as promising, I think that's going to be a little more promising as they should be. You never know, but what they should be. It would do such a disservice to patients for this drug to be priced, even at the level of Nexlatol. Again, Nexlatol is an inaccessible drug. To me, it's a donkey-ass drug. $6,000 a year for that drug, it's just not worth it. That's why we have a hard time finding a place for it for that reason in the clinic. It's really limited the statin-tolerant patients that don't want to take injections. And it stinks. It barely works. Like it's just a weak drug. Now, John predicted we are going to see big effects on metabolic disease. Okay, that was an easy prediction to make, based on everything you'd seen before it. But the other prediction he made was even more intriguing to me, which is, it might be, and I'm paraphrasing, but something to the effect, it might be that the most impressive thing about this drug is its effect on Alzheimer's disease. So tell me what it is that made you and John feel that way four or five years ago, and have you been validated in your predictions? Sure. It's very exciting for me to talk about it. When I came to New Amsterdam with John, John said, "Michael, I want to hear your story about Alzheimer's." And I said, "Let me go through it with you." Because we had, what we had at the time was a Mendelian randomization. We had the famous Bronx aging study, where people who, 400 Ashkenazi Jews, were close to 100 or older, they found out what was the most common gene, and that was CTP loss of function. So they had a CTP, and they had less. Then later came the data showing that if you have ApoE4, and you have a CTP loss of function, your risk of Alzheimer's is significantly mitigated. So we had genomics validation. What was the phenotype lipid-wise of those patients? Well, they have high HDL. These are ApoE4 patients who phenotypically have very favorable lipid profiles. But until you do the genetics, you wouldn't know it's due to. And they have very low, small LDL, and they have very high, large LDL particles. I mean, it's what CTP inhibition does. And so, Michael, what was the degree of risk reduction in those ApoE4 patients? Well, look at the curves. It basically took the ApoE4 risk away. Again, this is one study. And so they basically became the risk of a non-E4 by having the CTP loss of function. Wow. And that's a profound benefit. And then it's been validated by other genomic studies since then. We've done a lot of work ourselves on that. But also in Canada, at McGill, a PhD researcher had done some really great work on CTP. So you remember, the mouse does not have CTP. When you give the mouse amyloid precursor protein gene, they get amyloid and dementia. And then when you give them the CTP gene with it, it gets a lot worse. It's a lot worse. And then if you give the mouse a CTP inhibitor, you improve the dementia in that animal model. So they do nesting. Wait, wait. I'm a bit confused. You're saying you take a mouse that doesn't have CTP. CTP. And you give it a CTP. And you give it a CTP inhibitor? Right. Why would that change anything if they don't have it in the first place? No, no, but you gave them the CTP. Ah, got it. Okay. You gave the mouse the CTP gene. Yep. Then you block it. Giving CTP, first of all, made the dementia worse. Yes, understood. And then you give it the CTP inhibitor, it blocked it. Yeah. So we had that data. So when I started with John, I said, "John, can we study Alzheimer's?" And we went to our investors and they said, "Yes, you can have a slight amount of money to look it up." Unfortunately, in the biotech world, Alzheimer's does not. It's a huge graveyard. Yeah. And it's really hard to get funding for Alzheimer's studies. But we had another, obviously, the LDL and the cardiovascular. So we raised $200 million in our series A. We got $1 million allocated for Alzheimer's. We got $1 million for Alzheimer's research at the beginning. When did you go public? 2022. So we started the company in '21, early '21. We started the funding and then we went public in the end of '22. So that was the basis of our genomic data. We had the animal data. We also had a lot of data on HDL being somewhat protective against Alzheimer's. We had a lot of data on that. Mixed data, not entirely convincing, but a number of studies showed HDL, high HDL was protective against Alzheimer's, especially APOE1, which is the protein carrier for HDL. That's where we started. And so then with our funding, we were able to do a small study in Amsterdam, where we looked at about 13 APOE4 with impaired cognitive function, mild cognitive impairment. We gave them Ocetrapib and we saw some improvements in lipid metabolism. APOE4, by the way, is a lipid gene. Let's back up and let's talk about what about APOE4 is detrimental. I think there's a lot of data out there. APOE4 is detrimental. I mean, that's the key. Because you're talking about where does Ocetrapib fit in? We have the LPL, we have the diabetes benefit, the small particles, but also the fourth leg of that is for APOE4, you also have high LDL as well and lower HDL. So it becomes another good drug to consider. That's 25% of the population. So you can see where Ocetrapib becomes a really good add-on to statin option if you have any of those characteristics. And so let's talk about the homozygous E4 patient. What is happening in their brain as a result of the homozygosity? Because again, it's a very subtle change in their APOE protein due to that gene. And how does it manifest itself in the brain? Cholesterol metabolism worsens. Right, right. Yeah, it's very complicated. And everything I'm saying is there's still a lot of gaps in our knowledge about what exactly happens with the brain. I mean, we ABAOA4. But first of all, the brain is a very cholesterol-rich organ. If you look at, don't hold me to exact numbers, but 2% of the dry weight of the brain represents 50% of your body cholesterol. And so you have tremendous amount of cholesterol in the brain, and then you have a lot of fat, mostly DHA. So fat and cholesterol make up a big part of the brain mass. I mean, it's a big part of what the brain is all about. And cholesterol is synthesized very avidly by the neurons during your childhood growth phase. And then after you become adults, the neurons stop making cholesterol. And myelin, by the way, is 50% cholesterol. A lot of cholesterol goes into making myelin, and then astrocytes are involved in making. to make cholesterol they're there to help repair neurons and also neurons are the wiring and the make the thinking and all that stuff that brain function does but the astrocytes are involved in the nourishment and the garbage collection all that stuff they're involved in maintaining normal brain homeostasis now the complicating thing is the blood-brain barrier completely separates off the brain lipid metabolism from the rest of the body there's no apo b in the brain there's no apo b it's all apo e and hdl in the brain there's no connection between ldl and the plasma and ldl there's no ldl in the brain so the brain has its own cholesterol metabolism homeostasis and the particles the lipoproteins in the brain are hdl like particles that have apo e and so apo e in fact if you do a liver transplant your apo e4 before the donor and you give somebody an apo e3 liver they still have a liver transplant and they still have a liver transplant and they still have a apo e4 in the brain the brain stays there's no connection i had no i had never even thought of that michael yeah so that's the connection do you think there's any clinical significance to that in organ transplant so the question is with gene therapy now if you could convert someone from a e4 to an e3 can you do it in the liver and correct the risk we don't think we don't think so we don't know it's still a thought i mean that's super interesting yeah so apo e4 there's a two three and four most people are three threes and there's a two three and four there's a two three and four there's about 20 25 percent or three fours and then about two percent so three percent are homozygote e4s so you force your homozygote about 10 times risk of alzheimer's the three four is about three times risk three threes are average and if you're two which is the best your risk is lower and you have longevity it's one of the best longevity genes to be an apo e2 so that's the breakdown so so when you have apo e4 what happened so apo e is made by the astrocytes it appears that they have impaired cholesterol efflux and lipidation when you have apo e4 and so the neurons don't get the same nourishment or they can't clear cholesterol it becomes toxic and once cholesterol becomes toxic there's something called 24 hydroxy cholesterol which can go through the blood-brain barrier 24 7 another cholesterol so the blood-brain barrier protects all that but there's one cluster that goes through it's 24 hydroxy or 27 hydroxy they can transverse the blood-brain barrier the apo e four patients have impaired clearance of cholesterol and then that sets up a toxic situation where it gets inflammatory and then amyloid and tau follow aloes alzheimer's first described alzheimer's it was amyloid plaques tau tangles and basically lipid deposits and so when you have apo e4 you can't clear the lipid as well and that sets up the whole alzheimer's cascade and then they get alzheimer's roughly when one four gives you alzheimer's about 10 years earlier so two fours 20 years earlier that kind of thing so it's a very well-established risk having the apo e4 genotype so that's the background about apo e4 and it's a lipid gene and what is important about obacetrapib is that we have that genomic data we have the animal data and then we know that hdl is the one lipoprotein that does interface with the brain we don't think a boy one is actually made in the brain it comes from the periphery a boy one being the protein yeah i thought it was made in the liver you're saying if the brain's apo a1 is made in the brain or made in the liver most of it we believe comes from hdl from the plasma not so not from the brain yep it may be made in the brain but we don't think so we think it's made and comes across the blood-brain barrier and so we know that for sure in the coronal plexus which is the blood-brain barrier interface and this is just mechanical it's because hdls are so much smaller than ldls right small hdls but srb1 which is the receptor for we talked about that is heavily in the blood-brain barrier and the coronal plexus so the only thing that really interfaces with the brain from the outside the brain is hdl and so having high hdl can help remove the excess cholesterol that apo e4s can't metabolize effectively and also we prove this it delivers antioxidants to the brain they're very important to reduce the inflammatory response we know that and also maybe dha even can be delivered by hdl but certainly it's acting like it does it's the removal system amyloid even amyloid can be removed by hdl so we believe that the hdl going up and interfacing with the brain can help mitigate the apo e4 related alzheimer's risk what about in the non-fours we think it's the same true i mean even obviously non-fours get alzheimer's but it's later it's later in life it's late 80s or 90s instead of 70s 60s or 70s even we think of the same things are happening because you're getting you stop making cholesterol in the neurons your neurons are dependent on on astrocyte cholesterol function and so forth and as you get older you know these things tend to get less effective so we think that that part could also be mitigated by by raising hdl through oba cetra pibs mechanism of action what do you say to folks who say aren't statins causing alzheimer's disease because if the brain's cholesterol depot is the entire body and we give a person a statin and we know that some statins can actually cross the blood-brain barrier shouldn't statins even though the clinical trials would suggest the opposite just on an individual basis is there some risk that statins would be driving alzheimer's disease i mean just the opposite actually i mean yeah i guess my question sorry should be why do we not see that why do we see the opposite in the clinical trials about not protecting against why do we see that statins protect against alzheimer's disease you could argue mechanistically but if they're lowering cholesterol and they make it into the brain yeah we're not sure i mean the big statin trial that looked at alzheimer's didn't show a benefit it did not work that's not necessarily the means that statins can't protect against alzheimer's which i think they potentially can but in the study that was done actually done it didn't work yeah it was a wash it didn't work but in a recent study analysis they showed that if you did have apoe4 and took a statin your dementia risk was lower but that's an observational study and that's yeah i think that's fraught with issues i prefer these secondary analyses on randomized control trials yeah yeah yes let's put that when people ask about this all the time and you can say at least based on observational data there's no increased risk of alzheimer's first of all i just want to get them over their hump that's not going to increase the risk of dementia because you hear that we really focus on that protection issue it's a hard sell to say it actually prevents against alzheimer's because we don't think it gets to the core reason it can't affect lipid metabolism in the brain the way opacetamol potentially can i think what we see in the forms of dementia you do typically see in secondary analysis a risk reduction with statin trials and i suspect that that is picking up the vascular dementia improvement and because these studies are not powered to look at lewy body dementia versus vascular dementia versus alzheimer's disease it's a bucket of dementia and so you're seeing this reduction in vascular dementia but it's just being counted as overall dementia but not pathology specific that's absolutely true i mean ldl is a dementia risk factor but it might not be an alzheimer's risk factor that through this mechanism it's a stroke benefit so we think that obviously the elbicentropib having ldl lowering can benefit stroke but also we do believe or hope that we can show an alzheimer's prevention benefit talk about what we showed already but we're playing another study to look at it more carefully this year to look at the benefit of elbicentropib on prevention of alzheimer's so let's talk a little bit about what you saw in your biomarkers to kind of validate all of these hypotheses the first study that was a pilot study showed that we did in fact reduce 24 hydroxy and 24 7 the sterols in the csf went down you're not seeing that with statin so it was a difference and sorry how did you did you by csf right we measured csf in these patients and we saw that the 24 and 27 hydroxy went down we saw stabilization of biomarkers and we saw cognition stable we also saw had a few anecdotal cases of patients really having quite a benefit of elbicentropib on prevention of alzheimer's an official effect on cognition it was a pilot study with not power open label but we saw target engagement with 24 and 27 hydroxy going down we also in another analysis showed antioxidants in the csf going up we had target engagement that we are in fact removing these potentially toxic sterols and improving antioxidant levels in the csf so that's a proof of concept study that we did tell me about those patients did you say those had mci mci all had mci yeah and just explain to folks clinically how patients with mci would be behaving they do a cognitive testing there's all different types of scoring systems but when you do the memory testing and functional testing they score showing they have impairment but what's important about alzheimer's and why we're focusing on it is that we're learning now the abnormality starts 20 years before there's even mci there's a long lag period between when we start seeing the pathology the amyloid and the tau and all the biomarkers going up and actual mci and mci of course then has different levels until you get to the functional impairment where you're now this is actually subjective cognitive impairment where people think they have impairment when they do the testing they're still pretty okay and then you have those that are truly cognitively impaired yes so just so folks understand what we're talking about here which is alzheimer's is not a disease of old age it's a disease of middle age that presents in old age and that's saying exactly what you just said in a different way. I mean, that's in some ways a frightening thing to think about, but it's just the reality of the disease. And it also speaks to the lens through which we want to consider prevention. I would argue the same is true of cardiovascular disease. It's a disease of middle age. It presents in old age for most people. Unfortunately, for someone like your father, it presented in middle age, but it starts effectively the moment you've got these LDL particles circulating. And so what would you say is the canary in the coal mine that is measurable? Would you say that it is the presence of P-tau? Yeah, that's what's exciting about the field right now. Like I said, I came from the LDL world. Your LDL became a great causal. When I was involved, they weren't even sure LDL was really treatable when I started. I mean, they weren't even sure that you could reduce LDL and prevent heart disease in the 80s. I mentioned already, once you already have heart failure, lowering LDL doesn't seem to matter anymore. With Alzheimer's, I think we're seeing the same thing. Once you have MCI, and once you already have functional impairment, it's already too late. The brain is already shrunk and you got neurodegeneration. And so I think we're way too late in how we treat Alzheimer's. So we can find out prevention therapy. And do you think that's why your statement earlier about how much this is a graveyard for pharma is basically the case, which is, on the one hand, it's very difficult to develop drugs for primary. Because the trials would take too long. So you have to treat an active disease. But in this particular disease, if you treat the disease as dementia, you're hosed. It's almost like head cardiologists had the misfortune of trying to use lipid lowering therapy to treat heart failure. We may never have developed lipid lowering drugs. That's right. They would start with heart failure. It would all have been failures. We did heart failure trials and it didn't work. So with statins. So that's kind of the interesting thing, isn't it? Right? Which is with Alzheimer's. With Alzheimer's disease, we don't have the equivalent of the MI, the survivable MI, where if you intervene from a secondary prevention standpoint, we can develop those things. Because all of those tools that were developed for secondary prevention can now be deployed for primary prevention and have the maximum impact on saving lives. So it's a very unfortunate consequence of the pathology, though an understandable mistake on the part of pharma, because that's the hand you're dealt. You have to do clinical trials. Right, right, right. I hope that PTAL 217. PTAL 217, which is what we found, can ultimately become a biomarker for regulatory approval. It's just we're not there yet. How does it differ from PTAL 181? And let's talk about them through the lens of a little bit what they are biochemically, but also what do you think is the difference clinically between when you're measuring PTAL versus AB4240 and some of the other biomarkers that are becoming more common now? Sure, sure. It's a little bit of a background on these biomarkers. So they're all, when we did our first pilot study, PTAL 217. PTAL 217 wasn't available. We had 181. We had other ones. We convened a big advisory board of Alzheimer's experts. I'm not an Alzheimer's expert. I'm trying to become one now, of course. The panel said, this is a new biomarker called PTAL 217. If you can show over a year with our existing study within Broadway that you're reducing PTAL, that would be a great validation that what you saw in your pilot study is truly an effect. That's what we did. So PTAL 181 and 217 are both testing. PTAL measurements, but they correlate with amyloid in the brain. They're very strong predictors of amyloid on PET. And so if you look at centaloids of amyloid, which is the gooky stuff in the brain, the protein aggregates and so forth, the misfoldings, the amyloid, TAL 217 and 181 predict that very well. In fact, in some ways, I think the PET could be archaic relatively soon based on these biomarkers. That's a big deal given the radiation and the cost associated. Right, right, right. From my look at the literature, I mean, they're as good as the PET almost on area under the curve. So they're very good at predicting amyloid on the PET. They're very good at predicting progression of disease from normal to MCI. They're very good looking at MCI to full-blown stage two or three Alzheimer's. And even progression of Alzheimer's is also predicted by PTAL 217. So PTAL 217 occurs a little bit earlier than 181. So it's a little bit earlier in the process. So it picks up earlier. There's also a new one called brain-derived PTAL, which is maybe even better, but that's still early. So that's a TAL. It's amyloid first and then TAL. And there's this conversion of amyloid to TALopathy, which is a critical transition in the disease process where the amyloid is that gooky stuff and then TAL itself is the one that really drives the neurodegeneration that occurs later. So it's first amyloid. then a lot of tau, and then you're basically, unfortunately, it's too late. P tau 217 is not a CLIA approved assay, is it? Well, this 217, yes, it is CLIA. It is. But it's divided by amyloid 40, A beta 40. That got approved this past year. Sorry, you mean the ratio of- Of P tau to amyloid is approved. It is approved. Yeah. Okay. So AB 4240 is CLIA approved by itself? Right. P tau 181 is CLIA approved by itself? Yeah. If it's not approved already, it'll soon be approved. It's being used a lot. 217 not by itself, but in ratio is an approved- Right, right. Okay. And do you think that the ratio of P tau 217 to AB 4240 offers a benefit over P tau by itself? Well, the data's actually kind of mixed. There's actually P tau 217 alone looks awfully good. Whether the ratio is better, I've never- So you guys did your own assay for that? Yeah. We do standard assay for P tau 217. It's called- it's quantaric, which is one of the standard ones. There was something called prescivity, which does the P tau 217 with A beta 4240. But we look at all the biomarkers. We looked at P tau 217, P tau 181. We looked at GFAP, which is- I call it glial factor activation protein. It's not the right name. It's glial febrile acidic protein. It's a glial activating biomarker. Also very good. And early disease protection. And then we had the ratio, 4240 ratio, the nofilament light, which is a later stage inflammatory biomarker. And we see a lot in injuries, but as well as multiple sclerosis or ALS, those kind of things. But it's disease in Alzheimer's too, but later in Alzheimer's. We had our whole study, Broadway, 2,500 patients. And we had a sample that we could do. It was pre-specified analysis. We did analysis at the beginning and then 12 months at the end. And we looked at all of these biomarkers, with P tau 217 being our critical one to look at. We found that overall there was a reduction in P tau 217 going up in the overall population. But which I think is most exciting is that if you look at, we were worried about the most was that we had a population of heart disease patients that were not that old. The average age was 65. Are we going to really see anything in a year? Because if you know the data on these biomarkers, it takes many years for these things to turn. To transition into something really advanced. And so that's the key. But even low levels of these biomarkers are really very predictive of future Alzheimer's risk. And so what we found was overall it worked. If you had people that were older, it worked even better. If you had people that had E4, it worked even better. And if they were 4/4, homozygotes, we saw this profound benefit on not just P tau 217 over 20% difference from placebo, but all the biomarkers improved. Immunoid 4240, GFAP, neurofilament light, all got better with Obacetrapib. And that's what we published in our paper. So we felt that this data really confirmed that Obacetrapib was in fact active in potentially preventing Alzheimer's disease. Now, how do we know how to interpret whether those will end up being, maybe the answer is we don't. But do we have a sense of if this could translate to a clinically meaningful benefit? To a reversal of disease, a halting of disease, something of that effect? Or is it your belief that that could probably only happen if we establish causality through trials like this? And then take the same playbook that we took with cardiovascular disease, which is move up 20 years, start treating before any of these things are even remotely present. And just hope that that alone prevents even the development of the pathology. The answer is I don't know. The field is evolving and the regulators have to help out here. Right now, PTAL 217 cannot be an endpoint for regulatory approval. It does require improvement in cognition, which might be an impossible thing to show. Unless you took for decades. What we can say is that for us, we're going to go ahead with another study. We do know that the ApoE4 community, there's a new alliance of patients out there that are advocating for treatment. It's like any genetic disorder. They don't want to wait 10 years. They want something now for treatment. Don't you think it'll just be used? I don't think it'll be used off-label for that reason anyway. Well, we can't, unfortunately. You have nothing to do with that, but I'm just saying like, look, people were using PCSK9 inhibitors off-label for LpA reduction the moment it became clear that it was lowering LpA 20 to 30%. Now, we have no idea if lowering it 20 to 30% mattered, but it seems that it's not unheard of for people to take off-target use. There are plenty of people using GLP-1 agonists today for neuroprotection, even though that would still be considered sort of off-label as well. Yeah. Unfortunately, I can't talk about that. I've talked to a biotech company about off-label use, but I think the key is that I think PTAL217, with enough advocacy, can become a regulatory endpoint for this reason. is so good. Let's take the flip side of that. The Feynman argument that in science, the easiest person to fool is yourself, or the goal of science is not to fool yourself, and you're the easiest person to fool. So what would be the flip side argument? What would be the case for P-tau ultimately does not translate to clinical benefit? What would be true? If we had a crystal ball that showed us that, what would you sit here and say today as to why? What would the explanation be? You're proving a biomarker, but you're not treating the underlying disease. But it is the disease. I mean, that's the actual tau that's in the brain that leaks out into the plasma. So if we're using these anti-amyloid antibodies, or now they're working on anti-tau antibodies, and they've still got a ways to go, obviously those anti-amyloid antibodies have some very modest benefit, but not for APOE4 homozygotes. So I do feel that the homozygotes in particular, which are the ones that we know 100% go on to get Alzheimer's if they live long enough, like a lot of other rare diseases allow these surrogates to get approval. It's not a surrogate, which may or may not translate to a clinical benefit. Yeah, I'm thinking less of it from a regulatory question and more just from a biologic question of it's easy to get fooled. We can all be fooled. I mean, HDL fooled everybody for decades. For decades, people were chasing the wrong thing, and they had all the epidemiology to back it up. But at the end of the day, it didn't matter. I'm not saying this is the case. I'm not even suggesting that it looks likely that that's the case. I'm just saying that it's the case. And I certainly hope it's not the case. But I always find it interesting to imagine if we're sitting here in 20 years having a podcast talking about, oh, that whole P-Tau thing that took us down a rabbit hole. What a waste of time and money that was. We didn't save a single life. I wonder what the story would be. What would be the revisionist explanation of that? Here's what I'm also saying. In the last few months, there's been some supportive data that came out that's helpful. One is the GLP-1 trials, Evoque and Evoque Plus. No improvement in cognition, no effect on P-Tau-217. On the other hand, the Trailblazer anti-amyloid trials, Lilly, showed a pretty high correlation between improvement in cognition and P-Tau-217 going down. We're getting more data, and we're going to do our own study. We are going to do a study with 300 patients that have pre-Alzheimer's, you want to call it. They have evidence of higher Tau levels based on their ApoE. With MCI? No, not yet. We want to get it before. Like I said, we think MCI is too late. And so we got to get it before MCI. MCI is like early heart failure. Right, right. We know the brain has already shrunk and all that stuff. Inflammation has set in. The cascades, the talopathy is already well underway. I mean, so we can't wait that long and hope. But we can hopefully show that with our next study, we confirm all this. Even though it was not a prospective trial, it was a pre-specified analysis. We confirm all this, especially in the ApoE4 homozygote patients, the profound benefit. What we got most feedback from was, it's just the status is too good to be true. How can this be true? It was only 30 patients. It had homozygote E4. But it was so statistically significant. It was accepted for publication and all that kind of stuff. So the question is, what do we need to do to convince people? But right now, the world, the Alzheimer's world is very fixated on amyloid. I am surprised to hear that, Michael, given the number of bullet holes that have been fired through so much of that, right? I mean, including some of the fraudulent work that was done in the last decade. On this front, why do you think that they're still clinging so hard to that story? It's all about hope because it's such a devastating disease. I don't want to comment on the anti-amyloid drugs because it looks like some of the data might be encouraging, but it's a tough sell. Even you got to take it. You got to worry about brain bleeding and all that kind of stuff. It doesn't work on homozygote E4 either. Because of ARIA or it just doesn't? ARIA. ARIA is what I'm talking about. It doesn't work as well on the cognition improvement. I mean, that's- And you have the higher risk of- And you can use it in E4 homozygotes. That could be the same question. Is it that anti-amyloid drugs could be beneficial, but they have to be started 20 years sooner? And that's what they're trying to do. I mean, they're trying to go earlier. I don't know if it's early enough is the question. Can you really convince somebody who's 40 years old, whatever it is, to take an infusion to prevent amyloid? Especially if the side effects are potentially catastrophic. Yeah, right, right. So that's going to be a tough sell. So we're trying to find over six, we're trying to pick maybe age 60. Because we know from our Broadway data, who are the rapid, rapid progressors? Who does tau go up the most in? And it is obviously E4 is the older, even the diabetes that makes the amyloid. So I think that we'll do another study. And then hopefully that'll set the stage for a phase three trial where we could look at conversion of normal MCI preventing that conversion. That'll be a long-term study that we hope to do, pending the results of the next trial. Well, this is incredibly exciting. So again, the hope here would be that we see approval in the United States following the European approval. By a period of a year or two for cardiovascular disease. And in parallel, we see the right clinical trials being done on AD prevention. And this would make it a first. There would be no approved drug out there for AD prevention. Yeah, there's so much more we could talk about on this. But I do want to spend time on a topic that we talk about from time to time. But I have a feeling you're going to add a lot of value to my somewhat limited knowledge, which is the most up-to-date thinking on the role of AD prevention. I think the cardiovascular part, I'll give a quick answer to that, because I was involved in developing a omega-3 for heart disease called epinova. We went to an outcome study and it didn't work, but it was DHA and EPA, but mostly EPA had some DHA. And that was four grams? How much? That was four grams, yeah. It was called the strength trial. I think what I looked at was learned, because I've always been a big advocate for omega-3s for triglyceride lowering. And there's really two reasons why omega-3s can reduce risk. One is triglyceride lowering, and the other is by antithrombotic effects. EPA antagonizes the arachidonic acid pathway and has like a antithrombotic effect, anti-inflammatory effect. And so there was really two reasons to think why omega-3s could lower risk. And one was through the EPA antithrombotic effect, the other is triglyceride lowering. And so what strength was set up to do was, you know, we're going to really do a triglyceride lowering trial, and it didn't work overall. There was a hint of benefit in the secondary prevention arm, but it was 50-50 primary. And so if I had to do it all over again, I would have made it all secondary, just like mostly the REDUCE-IT trial was, which is the EPA-only trial. So the REDUCE-IT trial showed a benefit, and it could have been, likely had some effects of the mineral oil placebo, tilting it a little bit. I've heard this explanation before, but say a little bit more about why mineral oil as a but you'd actually look at the inflammatory signaling and increase inflammation. And so it had some inflammatory, Paul Ridker helped now analyze that from the REDUCE-IT study. It also may have affected absorption of statins because the LDL levels went up. LDL's level went up about 10%, so 9 to 10%. I think it showed that EPA works. EPA works. It may not have been the 25% that people think it was, but it still worked. You take all that away, it still worked. EPA only worked. And then- And the STRENGTH trial didn't work overall. It may have worked on secondary prevention in a, not post-hoc, but in that population. And the placebo in STRENGTH was what? Was corn oil. I see. Just so folks understand what we're talking about here, in the EPA-only trial, the placebo was mineral oil, but the hypothesis was that the mineral oil itself probably increased events slightly, which made the EPA look better alone than it might've been. But in the combined trial, the DHA-EPA trial, the placebo was corn oil. So you're doing mineral oil, inert, and you're doing apples to apples in terms of- Yeah, corn oil might have its own. We had a hard time coming up with a placebo, because it's not easy to find an oil placebo. Mineral oil, it isn't truly inert, but it does have that intestinal effects. I think the mineral oil controversy is, I still think reduced it shows a benefit for pure EPA. And then we had the PROMINENT study, which is a triglyceryl-lowering trial with a fibrate. Pimofibrate showed no benefit. It's very similar to the STRENGTH trial population. What that says is that EPA doesn't work. It doesn't work. It doesn't work. It doesn't work. It does work on reducing events- But not through triglyceryl-lowering? No, not for triglyceryl-lowering. It's more for the anti-thrombotic, anti-inflammatory effect, which brings me to DHA. So DHA, I still think has a lot of health values that we should talk about, especially for the brain, because the brain is predominantly DHA. That's the fatty acid in the brain. Now, the problem is with DHA, we tried DHA supplementations on cognition, didn't really show much. You had Hussein Yassin here, and he's talked a lot about. Well, one of the other things is they don't get as much DHA to the brain. They have a true DHA deficiency in the brain to some degree. A new discovery, which is very exciting, is the MFSDA2 transporter. MFSDA2 transporter. It's a transporter across the blood-brain barrier for DHA. It turns out that DHA prefers the lysopc form, the lysophosphatidylcholine form of DHA. That's the preferred substrate for DHA to cross the blood-brain barrier. Now, for the first time, you can now get lysopc-DHA. It's coming. It's on the horizon. We're actually, as part of Jocasta, we're going to be doing studies with lysopc-DHA on getting across the blood-brain barrier. Completely independent of the cloth at work. Right. Exactly. Yeah. That's coming. I've been on omega-3. One of the things that really, until this receptor was identified, we couldn't understand why DHA doesn't get into the blood-brain barrier like you think it. Most of your day-to-day has to come from the blood. It has to get there. It has to get there. Your brain cannot make that much DHA from other fatty acids, if at all. I mean, I think it can make some, but you have to get DHA from the periphery. So your belief today would be that if an individual is not consuming much fatty fish, you measure their red blood cell membrane concentration of EPA and DHA, and it's very low, 4%, and they were to supplement with a very high quality over-the-counter EPA and DHA, and they were to get that to 10%, your belief is they are probably lowering cardiovascular disease risk, but probably not having an impact on Alzheimer's disease risk, given the inability to get the DHA in the brain? You have to get the lyso-PC form to get to the brain. You have very limited capacity to convert that into the lyso-PC form. Yeah, absent another. Yeah, so you have to make this lyso-PC form, which you can do with. With either a fish-based oil or a krill-based oil, you can make lyso-PC DHA. So that's the next hopeful excitement around the DHA and brain health that I think needs to be further. But there is no version of that on the market today. Not. It's coming. It's coming, yeah. Yeah, but will it be a drug or will it be a supplement? No, there'll be a dietary supplement, yeah. Do you know who's making that? One is already available, krill oil-based, but there's one with fish oil-based coming. In Jocasta, we're going to do the science behind that as well. For a drug or for a supplement? For a supplement, yeah. Okay. You've been involved in so many clinical trials over the course of your life, and there's so much discussion about AI in medicine and the impacts it can have, but I'd have a hard time thinking of a more important impact that AI could have on medicine, that if it could speed up the time it takes to do a clinical trial by a log, and if it could reduce the cost by a log. So if you could take it from $4 billion a drug to $40 million, or frankly, if you could take it to $400 million, right, and if you could take it from 10 years to one year, you could change the course of human history. Where do you see AI factoring into what appears to be the long pole in the tent, which is doing clinical trials? It's a hard thing. Until there's regulatory reform, I hate to say it. I mean, I know that's a tough thing to advocate for because, first of all, you have to figure out, how do you do the data? It's still. Like, everyone's trying to say, "Can we make clinical trials a lot more streamlined, less data collection?" But also, to me, I wrote a paper about this. Why can't we look at clinical trials based on using AI who. If you took the drug the right way, how well did it work? Instead of, we have to get diluted by everyone who stopped the drug, who wasn't compliant. Yeah. So in other words, make the efficacy not based on intention to treat, but on actual compliance. Right. And that would be a huge difference already. Your effects are diluted so much by. Especially for long studies, you have to drop in. So you can use AI modeling even to show that for those who took the drug, took it the right way, the benefit worked well. When you look at a trial like either Broadway or ROSE II, what percentage of the patients enrolled in those trials do you believe were nearly 100% compliant? We actually. This is what's called on-treatment analysis, or kind of looking at PK, you know, who was taking the right drug. It all works so much better. But in a drug like a once-a-day pill, which is as easy as it gets for the most part, I guess maybe an injectable every few weeks would be similarly compliant. What is expected compliance? You want to see 80%. That's kind of the benchmark. Yeah. In fact, when you do your protocol analysis, you say anyone below 80% compliant. But the FDA will never accept per protocol analysis. No, no. Yeah. But they should. I mean, that's the thing. When I put it in this paper, I said, if we could find a way to streamline drug development, that's one thing. But AI could help a lot even more. I mean, we could do a study, instead of being 10,000, it could be 2,000. It just took the people that. Like, you get your log reduction. That's just one example. I mean, I don't know how much longer we can keep doing LDL trials with different MOAs. It's getting harder and harder to do these studies. Because of the ubiquity of drugs on the market already, and then the amount of LDL lowering that's already in the baseline? Right. You have to be ethical. You can't withhold treatment to patients. We have a lot of patients that can access to other drugs, and you just can't deny that to patients in a trial. It's going to be harder and harder to do these studies. So let's come back to statins for a moment. What do you think is the best explanation for the increase in the incidence of type 2 diabetes that we see in statins? Again, it's not small, but it's a real signal. I'm sorry. It's not large. It is small. It's a real and undeniable signal. And by the way, I would say that it's not just patients going on to get type 2 diabetes. It's insulin resistance. Patients who don't progress all the way to type 2 diabetes, we do see an increase in insulin resistance. What do you think is explaining that? Well, first of all, it's not just patients going on to get type 2 diabetes. Well, first of all, it looks like all LDL-lowering drugs, even PCSK9s, have a little bit of a diabetes signal, except for Obaceptrapim. I mean, just the opposite. Which is the opposite. Yeah. It is about LDL. But that's not entirely true. Don't bile acid sequestrants, which lower LDL, albeit somewhat weakly, show an improvement in glycemic control? Right. I published a paper on that, too. I mean, so, but I'm talking about the Mendelian randomization work. We look at diabetes and LDL. You see a consistent, except for the bile acid sequestrant part. Patients who don't progress all the way to type 2 diabetes, they don't progress all the way to type 3. So, I'm not sure what the drug matching for a gene would be, but it's not that often. If you can't do bile acid sequestrant, gene matching is not an easy one. But you're right. But bile acids are very energetic. They take a lot of steps to make a bile acid. So, you look at, when you have a bile acid removal, you got to make a new one. So, that creates energy requirements. So, you can see how blocking a bile acid from being reabsorbed, which is why you reabsorb it, so you don't have to worry about making it again, can ultimately reduce, potentially, blood sugar because it is lining up energy that you need to replace. That's my simple thinking about bile acids. Are there any patients that are in your clinic that are still on a bile acid sequestrant? Yes, there's some, yes. These are patients that can't tolerate any other drug or can't afford it? Well, they have hypercholesterolemia and they need, we have some, yeah. And how much LDL lowering do you get? About 10 to 15%. It's not great. And the side effects? The GI side effects. There's some that are better. We use them a lot. We don't use them that much anymore once the zetamide came into play. Because it's pretty much the same as a zetamide, but zetamide is a lot easier to take. And does a zetamide have an increase in insulin resistance associated with it? The data suggests, clinically, not. But I think, genomically, there is a slight signal there. The MPC-101, the knockout types, but certainly, PCSK9 inhibitors genetically have that. So, what do you think is the mechanism for that? I honestly don't know. I saw this recent data, which I think you talked about, where the change in the type of bile acids that you see, Yeah. could be a mechanism. But there's been other things, too. I mean, the beta cell preservation and so forth. I don't know. It's been an enigma about why. I don't think anyone knows for sure. But we do know a couple of things that I think are helpful. One, it is dose-related. It is age-related. It's weight-related. So, if you have those high-dose, older, obese, more common. To get our point earlier about not being on high-intensity statins, why is it worth the six, whatever it is, four to six percent? Why not? Why not go at a lower dose and lower risk? It's more about how do you mitigate the risk? Now, the MA, we haven't figured it out. I mean, this might be a reasonable explanation. But up until now, we haven't really figured out why the glucose issue is a problem. Yeah. Although, again, it is important, as we noted in our piece, that the asymmetry is still enormous. So, the risk reduction from the lipid lowering on cardiac events is a far bigger magnitude than the increase in the risk of. Type 2 diabetes, along with its expected manifestations of that. But the hope, of course, is that as more and more physicians become aware of that, understand it, move to combination therapy to lower statin dosing, I think it becomes less and less of an issue. That's the point. The net benefit is still so great. Unfortunately, it's a big discussion with patients very frequently. "I don't want diabetes. Why are you giving me this?" Your explanation is what we try to talk to them about. It's the overall net benefit is still. Yeah. very much in favor of taking the statin. How many other CTEP inhibitors are in the pipeline at the moment? To our knowledge, no others. We're at. If we're successful, there are going to be a lot more. But it's very hard to beat ovacetrapib. It's got a low dose, extremely well-tolerated in our clinical trials. Remind me, the molecule that, when you guys bought it, came from. Well, Amgen through Mitsubishi, Japanese company, first discovered it. It was sold to Amgen and we got. What were they doing? What was Mitsubishi doing when they were discovering it? Were they doing it specifically for the purpose of following the earlier CTEP inhibitors and then they sort of abandoned it after? Well, they wanted to make a better CTP inhibitor. So one that had no fat uptake, much lower dose, more potency, more bioavailable. And so they gave us. We got a great drug. We got a great drug to work with. It's going to be very hard to match the profile that ovacetrapib has from a pharmacokinetic perspective. And to give folks, again, just a sense of what does it take to develop a drug. So if you look at the money you paid to acquire the drug, what you had to raise through the clinical trials and what it would take to get to approval, what's the approximate dollar amount to do that? It's well over a billion, but that's not in counting what it was cost up until we got it. I mean. Yeah. It's a billion of New Amsterdam plus all the money that came before it to get it into phase two. Yeah. So the average drug right now is about $3 to $4 billion to approval. That accounts for the failures too, but it might be even more if you account for the failures. It's a lot. It's a lot of money. Like I said, it's a high risk, high reward investment. So been able to get to this point and we're hoping to have the drug to patients as soon as possible. What do you think overall of the landscape of biotech investing. I mean, we live in this world now where AI is clearly the most interesting and exciting thing to invest in. Capital is flying into AI. It doesn't really matter that lots of people are saying, hey, look, this is a bubble. We need to be a little more cautious with how we do this. This feels like 1999 for the internet, et cetera, et cetera. But it's so interesting when you look at biotech companies that, I mean, it's very, very difficult to raise money. Where do you think we are in the biotech life cycle? And do you think biotech is just forever going to be complicated because of the time horizon? The latter is true, of course. But what's really important is the macro issues is that we have all these big pharma companies that have big sales forces and companies, and they have pipelines that are the big, big gaps and the patent cliffs are coming. All of them, in order to grow, they have to get new product. I think in the way the system is set up, you know, everything ultimately goes generic. And so if you see where that is, if companies even want to grow three or four percent per year, which is pretty minuscule growth, they got to add a lot of new products to their pipeline. The way it's worked out is the big companies also have become pretty dysfunctional on innovation about developing new drugs. The small companies can be a lot more nimble, a lot more flexible, take more risk, and don't have to worry about corporate kind of hierarchy to make a decision. We feel that biotech is right now in a really good position, and I think AI is going to help a lot. I hope we can figure out a way to make clinical trials a lot more cost-effective and lower cost, but even drug discovery. China, for example, has just become a huge investment, and for every chemist in the United States, just like 10,000 in China. They have the capabilities to really surpass anything that we can do from a drug development perspective, just by the person power that they have. But that sets up a lot of new opportunities for us. I mean, I still think we have the science and the innovation, and we have the creativity that could lead the world in coming up with the new ideas. But China is going to be able to take it to the next level to how they get a drug produced, make it to the human data as quickly as possible. Clotho is a good example. I mean, the hardest part about Clotho before we got involved was no one could manufacture it. No one could make it effectively. Then we went to China, Wuxi, and they figured out a process. And now it's a very robust process, and it's going very well. So we hope to be in human clinical trials pretty soon. If you look at it from a global perspective, if everyone could work well together, we have the makings of a biotech revolution, but we continue to have a high benefit to risk ratio too. I mean, so we have to see how that plays out. Well, Michael, this is really exciting. I love when we can sort of string together podcasts over a series of years and get kind of an update from one very exciting idea to another. I was impressed by the way you did that. I mean, I think it's a great idea. I think it's a great idea. I was incredibly excited about Obacetrapib when we spoke about it the first time with John, and everything you've updated us on today only makes that, look, we just can't wait to get this drug into the hands of people. And hopefully not just for cardiovascular disease, but perhaps even more excitingly for Alzheimer's disease, especially in those E4 patients. Anything else you want to talk about on the Clotho front? I know we didn't spend too much time on it. You and I are both involved, which is why I'm a little bit coy to talk about it. I don't like to talk about things that I'm directly involved in as well. Right. It's moving along well. Like I said, the Chinese, the Wuxi made a great protein. What we decided, just to kind of step back where we were a couple years ago, we had this genomic validation that if you have the Clotho gene, you're protected against Alzheimer's, E4 in particular. We had this great animal data consistently showing that if you inject Clotho peripherally, you improve cognition. It went to a primate study and showed great data. And the primates got published in Nature. I'm a journal. We believe we had well-validated target and drug, but the missing part was the MOA. No one knows how it works. And by the way, that's a painful point, right? I mean, there's only about 3% of FDA-approved drugs do not have a clear mechanism of action. Yeah, metformin doesn't, is it? Right. Tylenol. Yeah, right. We have other examples of where the MOA is not known. So when you and I embarked on, okay, how are we going to get this to humans? What we had decided to do was we basically, we have to sort of give up on trying to get this to humans. We have to give up on trying to figure out the MOA exactly, because we just have to find people willing to fund the studies up until human data and prove that it does improve cognition and a human trial. Then I think it's going to be hopefully a solid going forward. Not just hopefully Alzheimer's as a treatment for Alzheimer's disease, hopefully even a prevention too, because it does have all those criteria. We still don't know the MOA. We do think that the latest is that the full length, yeah, the full length, we're going to have a new fragment that may be cleaved that does cross the blood-brain barrier. That could be the mechanism of action. We know that peripherally giving it does improve cognition. We're getting closer. Now the supply is in place and we're starting the trials to get ready for the IND filing that, you know, the official hope to have human data in roughly a year from now. So we can come back and talk about that with maybe Dina together. We can talk about the benefits of cloth though. Yeah, it is. It's very high risk, but I know so many of, obviously, the investors in Jocasta, and many of them really come at this through the lens of this is partially a financial investment, but many of them also think of it as philanthropy without the tax break, which is, I'm not just putting my money into this company because I want to make money. That would be great. But what would be greater is if this drug actually works. And I feel like a lot of people take that approach in biotech, especially when it comes to a disease like Alzheimer's disease, where we're just watching people suffer so much right now, nothing to offer them. We have to keep working at it. I just lost a double first cousin. My mother's brother married my father's sister. So we have all the same grandparents. She just died at age 72 of Alzheimer's. He was an E4. I've seen it. And I've seen, of course, a lot of patients struggle with it. And I wish we had better advice about what to do. But we do know, I do think maybe we should end with is, what do you do? What if you're an APOE4? There are some that say, don't even bother checking it because what can you do about it? I think that's the wrong approach. I mean, knowing you have it, you can obviously better lifestyle, exercise, taking some DHA. Even though you may not get enough into the brain is still, and then keeping your obviously no diabetes. Normal blood pressure, not smoking, managing lipids. Yeah, there's a lot you can do. I agree with you. I find it very frustrating when people suggest, and by the way, I totally respect a person who says, I don't want to know. Totally fine. Would never force that on anybody. But to suggest that knowing that couldn't provide the motivation to do the things that are hard to do when you're 30 and 40 years old, long before this disease takes hold. I think that's probably the wrong side of that bet for me. But at the same time, I do see a lot of people going too far. And I would almost put myself in that camp of where I was maybe four or five years ago, trying to look too much at biomarkers that I think in retrospect probably weren't important enough. I think when you're looking so hard for things, you start to make signal out of noise. And I also think that that can create too much anxiety. And quite frankly, I can think of at least two examples where a patient suffered more anxiety than they needed to over something that I just don't know that I would take to the bank as an actionable and treatable and modifiable biomarker. So I'm pulling for Klotho, I'm pulling for Obacetrapib. And then of course, if they're successful, what that's going to do is open up the door for more things. But what I love about the two of them is potentially they're working by a different mechanism. So I love when you can go after complicated diseases from multiple vantage points. And it's clear we're going to need multiple therapies. That's the thing. Obacetrapib alone could be a preventive strategy. You're going to need more. You need something else as well to make a difference. Well, Michael, thank you for the amazing work you're doing. And thanks for taking the time to come out here today. It was so much fun talking to you. Yeah, so much fun, Peter. Thank you. Thank you. And they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active list of all disclosures.