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

Welcome and show introduction

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Meeting Michael Davidson

1:04My 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 a thousand 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

1:38Chicago 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,

2:09LpA, 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 member, LpA, diabetes risk, and cardiovascular outcomes. How Obacetrapib may fit alongside statins, ezetamide, PCSK9 inhibitors, and other lipid-lowering therapies. The complicated

2:44biology 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.

3:13Michael, 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

3:48prevention-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

4:19niacin 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 still have cardiologists, 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

4:53that did all the clinical trials. And that's been my path ever since. And then the biotech startups started happening about 15 years ago.

Primary prevention and causality

5:02We 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 people look at me as though I have multiple heads when I talk about taking steps towards prevention in 30-year-olds,

5:32for 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

6:04before it's there. And 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 to someone who 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

6:39attack 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 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

7:14disease. 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

7:45risk 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

8:17father-in-law. My father-in-law's father, whenever my wife's grandfather, also died at 47 in the hands of his 16-year-old son. 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, 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.

8:48And my brother, who's also a family doctor, went on 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

9:19to 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 theory. 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. 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 it that I

9:55would 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

10:30everyone 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, it's probably 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

11:05I 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 randomizations, 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

11:41the 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

12:14effectively. 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

12:49become so contentious? Multiple reasons, but one actual reason I think is that people believe that LDL cholesterol can be totally managed with lifestyle. 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

13:19genetics, there's nothing they can do about other than they're already doing great lifestyle and so forth. That becomes, I think, part of the motivation to get them to do something about it. 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

13:51to 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

14:22weight 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

14:55Obacetrapib. That 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

History of CETP inhibitors

15:11feasible. Let's talk a little bit about Obacetrapib. 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.

15:42Let'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 eight. Okay. About Treceptor 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.

16:16So it's all right. So first, this was Pfizer combining this with a torvistatin in a clinical trial. Okay. Go back from that a decade into the discovery of yet another mechanism. Cause 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. So we're going to come and talk, I want to come back and talk about bile acid sequesterins. We

16:47probably 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 CTP 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 CTP, like the rat,

17:20the dog, they have very low LDLs, very high HDLs. They don't get atherosclerosis unless you give the rat or the mouse CTP 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 CTP. Monkeys have CTP. Rabbits have CTP. Humans have CTP. We have, relatively speaking, high LDL, low HDL. So in effect, one of the most prominent atherosclerotic animal models

17:51is to give the mouse CTP. And that's what we use in a lot of our studies to show that you can induce atherosclerosis and a different therapy 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

18:22a 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. So animals that had more scarce nutrients would want to hyper-conserve cholesterol. I mean, almost all, let's say, vegetarian animals don't have CTP. So if you look at it from that perspective, we're meant to be a vegetarian maybe. So that's how you think about how CTP

18:53plays 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 CTP, 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 CTP. 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

19:26HDL is high, you're protected from heart disease. They use 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 about raising HDL. And where were we in our knowledge of niacin's impact on HDL and events? We only knew niacin alone in the coronary drug project did lower

20:03events. We also knew niacin as one of the drugs that was studied. It had a lone, 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. 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,

20:34didn'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, so did not lower... Events. Events. The Thrive HPS II 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-torcetropib. So, torcetropib was the Pfizer CTP inhibitor.

21:08Everyone 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.

21:42So, torcetropib 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 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

22:14iceberg. The drug had a very prominent effect on increasing, getting through the adrenal glands, and it 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 torcetropib, and the blood pressure would go up dramatically within an hour, and they have no CTP. The rat has no CTP. So, that said, it's an off-target effect. And since then, there's been a lot

22:44of 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, no, Roche, dalsetropib. Okay. It was mostly off-target. Obviously, there were some that thought, okay, maybe the target's off. But

23:14that 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 that 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 on torcetropib 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

23:45developed other CD 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

24:20association? That's a great question, but there's a lot of work that went into the HDL function. You know, 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 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, and matures. It goes from this pancake up to a big

24:54ball filled with cholesterol, 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

25:27inflammatory 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

25:58compared 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 liver for clearance. Learned it's a lot more complicated than that, but that was our thinking back in 2006

26:28when torcetripib unfortunately kind of failed. And just to be honest where I was, I mean, I was a big fan of torcetripib 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 kind of thinking, okay, if any of 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 complicated than that as far as the side effect profile, yeah. How much did HDL go up with torcetripib? About 75%.

26:59Wow. 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

27:33no LDL effect. So 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. Reduced the risk of diabetes, but had no MACE benefit. Did not cause any MACE benefit. Major adverse cardiac events. You're 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

28:04failure, high profile failure. Actually went to another trial later. It's still neutral. No, no benefit on major adverse cardiac events. That's number two. And then MERT? Then Lilly. Oh my gosh. Then Lilly, which was evocetropib. 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

28:34opportunity to reduce heart disease. So it was all by 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. In secondary prevention. Secondary prevention. It was a high risk secondary prevention.

29:05By 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, ZETEF 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.

29:38Azetamide, 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, but after two years, they separated. And so the similar would have happened, we believe, with evocetrapib in the ACCELERATE trial. Although with Repatha and Prolulant, we did see benefit at about two years. This was only a 15% LDL lowering. Yeah, yeah, yeah, yeah, yeah. So it's also interesting, in the Odyssey outcome study, which is the Pryolin, which is the other PCS-CAD inhibitor, if you look at populations that had LDLs below 100, which is what this

30:12population, they also didn't separate until after two years. Same with Fourier, which one was more heavily... No, Fourier was Repatha. But which one was more heavily statinized? I can't remember. They both are pretty, but Fourier was not acute coronary syndrome population. Got it. It was a chronic stable. They sent a separate... The acute coronary syndrome population 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, Obocetrapib.

30:44That was the hardest one to explain. And what were the features of the Lilly drug in terms of HDLC and LDL-C kinetics? The Lord L did about 15% to 20%. And raised HDLC. 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?

31:16Well, it was largely cardiovascular, but it had some non-cardiovascular mortality. So when 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. Well, 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.

31:46So they had decided to cut the study short. Again, HDL raising, you would think, would have a benefit already. So it was the LDL lowering wasn't really thought of as the main mechanism. Did that study show any improvement in diabetes? It did also, yes. All the CT inhibitors, even torcetripib, showed a diabetes benefit. All of them. So this is, again, why we're focusing on that with ovocetripib 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.

32:17It 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 dalsetripib, 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 very large study. They went for four years. The baseline LDL was 60. So we're talking about already low LDL.

32:48They got a 17% LDL lowering, 11 milligrams per deciliter, absolute LDL lowering. 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 CTV 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.

33:20And 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. And it started...

33:50They didn't do the PK stuff? 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. They 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.

34:22But 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 stop, all of the secondary prevention

34:52trials, 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. 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

35:2417% reduction in LDL-C from 60 to 49, you would expect an event reduction on a relative basis of 9%, et cetera. Right, 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% melt-to-bris reduction. And that's largely linear. It's linear, right. But absolute is the key, not percent. You got to look at the absolute LDL-lowering, and then you can calculate the benefit.

35:55And we're doing that for our, obviously, our outcome study. We can have a predicted benefit based on our absolute LDL-lowering that we hope to achieve in our Prevail trial. You 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 are independent of how you do it. The Mendelian randomization says we're going to lower it genetically.

36:26It'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

36:59a role. They'll talk about pleiotropic 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, that was the one I 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-tolerated. 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.

37:29So with all of that as background, now let's talk about Obocetrapib, 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. And I had sold my previous company, an interleukin-6 antibody for heart disease, inflammatory. It's a, I don't know if you're familiar with 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 up. So I had sold Corvidia.

38:00And John said, let's get Obocetrapib 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 it? This is five, almost, this is our sixth year now. That's so interesting because Repatha launches in 2015.

38:30Right. They kept Obie on the shelf for five years? I think they bought it in 2017. They bought it in 2017. Interesting. They actually did a lot of great work on the manufacturing, the process. They worked on it, made it a much more cost-effective manufacturer, but they didn't do any clinical trials. They just kept it on the shelf. It already had an IND in the U.S. or this was all- It already had phase two data. In the U.S.? In the U.S., yeah. Okay. It was ready to go. So we initially thought about statin tolerance and using it for those patients as a quick route

39:03to the market. But we realized the FDA view on CT inhibition because of the history, we really didn't have a path there. The FDA does not like statin tolerance 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. Sure. In the academic world and in the FDA, they don't really believe it is a true phenomenon. Because if we look at the placebo-controlled trials, it's very low rates. It's about 4.9%. Yeah. But even true statin tolerance is very hard to find. I mean, it's in the trials.

39:34But 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 an 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 a TULIP study, which was the set of John had 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.

40:06Okay. So what was different about OB? It's a much more potent. And so it's only, the other CTP inhibitors are all in the 100 milligram plus range and they lowered LDL, as I mentioned. And you're at 10 milligrams. They were 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.

40:38And 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 it 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

41:09had nothing to do with the benefit of CETEP inhibition? Right, exactly. Okay. And other HDL-raising genes saw no benefit. At least the benefit could not be explained by the HDL effects. It was, 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?

41:39Yeah, right, exactly. Yeah, 15 years. 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, my, 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. You notice I really worked hard to avoid saying the term good cholesterol.

42:11I'm avoiding using that term because our mutual friend hates it, as we know, but it's the wrong way to phrase it. Yeah. 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?

42:43So HDL is really interesting. We believe it could still have some cardiovascular benefits if you raised 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 high 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

43:14and 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 HDL-C of 100, 110. And I was able to convince him, I said, you know, look, you're right, statistically speaking,

43:46your 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 HDL-C. So would you mind getting 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 lipid clinic that have the high HDL due to SRB1. There's anothelolipase.

44:17There'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 Obacetropib'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.

44:49So when John was on the podcast, again, I think it was four years ago-ish, but a lot has happened since then.

Obacetrapib clinical trials

44:55So let's talk about where we are today. What is the state of understanding of Obacetropib? 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 tandem, yeah.

45:25So we've now done two more phase two trials and three very large phase three trials, and they're all being completed and were actually filed in Europe for approval. In the US, we're waiting to time it on the outcome study called Prevail. 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. Now we have plenty of cash to finish the trial, the Prevail trial.

45:58So 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 ROSE 2. Both showed, again, the 45% to 50% monotherapy benefit. And then in combination with ezetimibe, you know, in that 55% range, higher, better LDL lowering. We then did what was called Brooklyn, which is a familial hypercholesterolemia trial. I know you've done multiple podcasts on this autosomal dominant genetic disorder, very high

46:31LDL, 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 stands. Many were on ezetimibe or PCS-Kin 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

47:07combination you're on, Obisetropib 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 atorvacet. They're all very well treated.

47:38And 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 Ezetamide, 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

48:10that 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 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.

48:42And 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 on ethic issues, ethical issues. So these are all on maxly 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 to stop the trial. One is that we have a minimum follow-up of two and a half years.

49:14Again, the learnings from the other trials. And the other is also event-driven. How many events to power the study appropriately 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.

49:45That 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 Obacetrapib 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 U.S. is a different story.

50:15Then 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 U.S., 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 II 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

50:47between 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. 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.

51:20You can see it more easily, because ApoB, LDL's 80, ApoB comes back 85. Is that really that kind of thing? You 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. Actually, no, we use the liposcience, yes. That was the assay that we used.

51:50Okay, 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 discordance between ApoB and LDL-P. And then there's a study done at the C- 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?

52:23What is the reason why you have a normal ApoB and a 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.

52:54The LDL-P is the NMR, the nuclear magnet is 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 know, 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. We're doing... 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,

53:26assuming 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's called non-HTL cholesterol, which is very close to ApoB. It's LDL plus VLDL cholesterol.

53:56We 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-HDLC 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. And discordance, you can get discordance with using non-HDL, ApoB, or LDL-P.

54:28I 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.

LpA lowering and statins

54:50But of course, what Obacetrapib has that we're also excited about is the LPLA 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 LPLA. 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 LPLA. We don't know the reasons, all the reasons why those drugs lower LPLA about 15 to 20%. But we were looking into this, we have done a clearance study.

55:21It does reduce production of LPLA. We've done an actual assay looking at, it's a study labeling LPLA 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 LPLA 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 LPLA? That is still in a phase three trial?

55:51Yeah, 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 LPLA 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.

56:22But when you have a patient who has high LPLA, they go, I don't want to be on a stat because it raises LPLA. And so what do we do? Well, the truth of the malady is you bring the LDL down, you really mitigate risk substantially. Horizon trial. So you think that the issue with that study was their LDL-C was so low that you didn't get enough events. So abolishing LPLA 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.

56:53I 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 LPLA 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 LPLA-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 LPLA era is getting started.

57:25I 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? Well, I want to say, again, your question is the right way to frame it.

57:55We 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 LPLA and it does not lower small particles very well. It lowers mostly the non-small particles.

58:27But does Obacetrapib do well? It lowers the risk of diabetes based on our Broadway trial data as well as other CTV inhibitors. It lowers LPLA in that 50% range in that moderate band. And it lowers the risk of diabetes, lowers LPLA and 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 issues mostly go away and it really is a good companion drug

58:59to a statin for that reason. Now we have the combo pill with azetamide, which puts us in the same range as the PCSKIN inhibitors or even the upcoming oral PCSKIN inhibitors. 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 pretty significant impact on transaminases, especially when combined with azetamide.

59:29And 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.

1:00:00I'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 resubastatin. 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

1:00:30virtually 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.

1:01:02Because 25 years ago, you didn't have Repatha. You didn't have Proluent. You didn't have Ezetimibe. You didn't have Bempadoic 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.

1:01:35So we believe that with OB alone and OB with Ezetimibe, 90% of patients are done. But they're 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 Nexlitol, I mean, it's as expensive as an injectable monoclonal antibody.

1:02:06So 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 Nexlitol? Unfortunately, it's all about access, not about price. That's the big difference. So we haven't decided on pricey. 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.

1:02:37So they don't put it on formulary. And so you've 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 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-berpatho was a huge example, right?

1:03:09I 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 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?

1:03:41It'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 to 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

1:04:13about 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?

APOE4 and Alzheimer prevention

1:04:27Sure. 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 minimization. We had the famous Bronx Aging Study, where people who, 400 Ashkenazi Jews, over close to 100 or older, they found out what was the most common gene, and that was CTP, loss of

1:04:57function. 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.

1:05:31I 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. So, that's a profound benefit. So, that's one. 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.

1:06:06So, 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, I'm a bit confused. You're saying you take a mouse that doesn't have CTP. And you give it a CTP. And you give it a CTP inhibitor?

1:06:37Right. Why would that change anything if they don't have it in the first place? 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 a CTP inhibitor, it blocked it. 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 out. And 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.

1:07:11But 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 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, the 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.

1:07:41Mixed data, not entirely convincing, but a number of studies showed HDL, high HDL was protective against Alzheimer's, especially APOA1, 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 APOA4 with impaired cognitive function, mild cognitive impairment. We gave them ovocetrapib and we saw some improvements in lipid metabolism. APOA4, by the way, is a lipid gene.

1:08:11Let's back up. Let's talk about what about APOA4 is detrimental. I mean, that's the key because, you know, you're talking about where does ovocetrapib fit in. We have the LPL-A, we have the diabetes benefit, the small particles. But also, the fourth leg of that is, for APOA4, 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 ovocetrapib becomes a really good add-on to statin option if you have any of those characteristics.

1:08:43And 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. 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 APOE4.

1:09:13But 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

1:09:45phase. 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, they continue to make cholesterol. They're there to help repair neurons. And also, neurons are the wiring and the making 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.

1:10:18Now, the complicating thing is, the blood-brain barrier completely separates off the brain lipid metabolism from the rest of the body. There's no ApoB in the brain. There's no ApoB. It's all ApoE 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 ApoE.

1:10:49And so, ApoE, in fact, if you do a liver transplant, your ApoE4 before the donor and you give somebody an ApoE3 liver, they still have ApoE4 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 so. We don't think so.

1:11:20We don't know. It's still a thought. That's super interesting. Yeah. So, ApoE4, there's a 2, 3, and 4. Most people are 3, 3s. There's about 20, 25% are 3, 4s. And then about 2%, so 3% are homozygote E4s. So, E4s, your homozygote about 10 times risk of Alzheimer's. The 3, 4 is about 3 times risk. 3, 3s are average. And then if you're a 2, which is the best, your risk is lower and you have longevity. It's one of the best longevity genes to be an ApoE2.

1:11:52So, that's the breakdown. So, when you have ApoE4, what happens? So, ApoE is made by the astrocytes. It appears that they have impaired cholesterol, efflux, and lipidation when you have ApoE4. 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-hydroxycholesterol, which can go through the blood-brain barrier, 24-7 and other cholesterol. So, the blood-brain barrier protects all that. But there's one cholesterol that goes through.

1:12:23It's 24-hydroxy or 27-hydroxy. They can transverse the blood-brain barrier. The ApoE4 patients have impaired clearance of cholesterol. And then, that sets up a toxic situation where it keeps inflammatory. And then, amyloid and tau follow. Although Alzheimer's first described Alzheimer's, it was amyloid plaques, tau tangles, and basically lipid deposits. And so, when you have ApoE4, you can't clear the lipid as well.

1:12:54And that sets up the whole Alzheimer's cascade. And then, you get Alzheimer's roughly, 1-4 gives you Alzheimer's about 10 years earlier. So, 2-4 is 20 years earlier. That kind of thing. So, it's a very well-established risk having an ApoE4 genotype. So, that's the background about ApoE4, and it's a lipid gene. And what is important about Obocetrapib 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

1:13:28the brain. We don't think ApoE1 is actually made in the brain. It comes from the periphery. ApoE1 being the protein carrier of HDL. Yeah, I thought it was made in the liver. You're saying if the brain's ApoE1 is made in the brain or made in the liver. Most of it, we believe, comes from HDL from the plasma. 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 choroidal plexus, which is the blood-brain barrier interface. And this is just mechanical. It's because HDLs are so much smaller than LDLs.

1:14:00Right, with small HDLs, but SRB1, which is the receptor, we talked about that, is heavily in the blood-brain barrier and the choroidal plexus. So, the only thing that really interfaces with the brain from the outside of the brain is HDL. And so, having high HDL can help remove the excess cholesterol that ApoE4s 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.

1:14:33But 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 ApoE4-related Alzheimer's risk. What about in the non-4s? We think it's the same true. I mean, even, obviously, non-4s 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, again, if you stop making cholesterol in the neurons, your neurons are dependent

1:15:04on 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 raising HDL through Obacetrapib's 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 most important cholesterol depot in 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

1:15:37the 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 Alzheimer's? Yeah, 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

1:16:09think 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, yes. 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 the hump that's not going to increase the risk of dementia, because you hear that. We really focus on that protection issue.

1:16:43It'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 the lipid metabolism in the brain the way obocetrapid potentially can. I think what we see in the literature, at least the way I look at it, Michael, is that when you look at all 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.

1:17:16And 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 through this mechanism. It's a stroke benefit. So we think that obviously the elbow centrapid 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

1:17:46this year, to look at the benefit of a centrapid 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 seven, the sterols in the CSF went down. You'd not seen 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.

1:18:18We saw stabilization of biomarkers and we saw cognition stable. We also saw, had a few anecdotal cases of patients really having quite a beneficial effect on cognition. It was a pilot study. It was 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

1:18:48improving antioxidant levels in the CSF. So that's a proof of concept study that we did.

Biomarkers and neurodegeneration

1:18:55Tell 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 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

1:19:31all 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, and this is actually subjective cognitive impairment where people think they have impairment, but 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

1:20:04disease. 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.

1:20:35Your 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 mean, so 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.

1:21:05So 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 prevention 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 had cardiologists had the misfortune of trying to use lipid-lowering

1:21:38therapy 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 it stands. So that's kind of the interesting thing, isn't it, right? Which is 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.

1:22:09So 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, which is what we found in our, 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

1:22:40versus 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 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,

1:23:12that 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 TAL measurements, but they correlate with amyloid in the brain. They're very strong predictors of amyloid on PET. And so if you look at centeloids 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

1:23:42well. 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 with those tests. From what I 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 at looking at MCI to full-blown stage 2 or 3 Alzheimer's. And even progression of Alzheimer's is also predicted by PTAL-217.

1:24:15So 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 kooky stuff and then TAL itself is the one

1:24:46that really drives the neurodegeneration that occurs later. So it's first amyloid, then a lot of TAL, and then you're basically, unfortunately, it's too late. PTAL-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, ABeta 40. That got approved this past year. Sorry, you mean the ratio of PTAL to amyloid is approved. It is approved. Yeah. Okay, so AB 40-240 is CLIA-approved by itself?

1:25:19Right. PTAL-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 PTAL-217 to AB 40-240 offers a benefit over PTAL by itself? Well, the data's actually kind of mixed. There's actually, PTAL-217 alone looks awfully good. Whether the ratio is better, I've never- So you guys did your own assay for that?

1:25:49We do standard assay for PTAL-217. It's called, it's Quanteris, which is one of the standard ones. There was something called Precivity, which does the PTAL-217 with AB 40-240. But we looked at all the biomarkers. We looked at PTAL-217, PTAL-181, we looked at GFAP, which is, I call it glial factor activation protein. It's not the right name. It's glial fibrillary acidic protein. It's a glial activating biomarker. Also very good at early disease protection.

1:26:21And then we had the ratio, 42-40 ratio, the no filament light, which is a later stage inflammatory biomarker. I mean, you see a lot in injuries, but as well as multiple sclerosis or ALS, those kind of things. This is easy 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 of all these biomarkers. With PTAL-217 being our critical one to look at, we found that overall, there was a

1:26:57reduction in PTAL-217 going up in the overall population. But, which I think is most exciting, is that if you look at, what 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 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

1:27:29risk. 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 PTAL-217, over 20% difference from placebo, but all the biomarkers improved. So 181, amyloid 4240, GFAP, neurofilaminolite, 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

1:28:06preventing 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,

1:28:37and 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 because 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

1:29:09advocating 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 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 LP-A reduction the moment it became clear that it was lowering LP-A 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.

1:29:39There 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 as a CEO of a biotech company about off-label use, but I think the key is that I think PTAL-217 with enough advocacy can become a regulatory endpoint for this reason. I mean, it's 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.

1:30:10So what would be the flip side argument? What would be the case for PTAL 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 TAL that's in the brain that leaks out into the plasma. So it is a measure. If we're using these anti-amyloid antibodies, or now they're working on anti-TAL antibodies, and they've still got a ways to go, obviously those anti-amyloid antibodies have some very

1:30:42modest 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 based on a surrogate that 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.

1:31:12I 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. 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.

1:31:44I 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, Evoke and Evoke Plus, and no improvement in cognition, no effect on P-tal-217. On the other hand, the Trailblazer anti-amyloid trials literally showed a pretty high correlation between improvement in cognition and P-tal-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

1:32:18it. They have evidence of higher TAL 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 is already shrunk and all that stuff. Inflammation is set in. The cascades, the TAL-opathy 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

1:32:50analysis. We confirm all this, especially in the APOE4 homozygote patients, the profound benefit. What we got most feedback from was, it's just, this data is just 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, Alzheimer's world is very fixated on amyloid. I am surprised to hear that, Michael, given the number of bullet holes that have been

1:33:23fired 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? Oh, ARIA. ARIA is what I'm talking about. It doesn't work as well on the cognition improvement.

1:33:55I mean, that's... And you have the higher risk of... ARIA. So they don't give it. There's supposed to be a contraindication to 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 like maybe age 60.

1:34:26Because we know from our Broadway data, who are the more rapid progressors? Who does TAL go up the most in? And it is obviously E4 is older, even the diabetes that makes the amyloid. So I think that we're going to 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 on 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

1:34:58European 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.

Omega-3 fatty acids and DHA

1:35:17But 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 fish oils, DHA and EPA. But you want to talk about it through cardiovascular disease first or talk about it through Alzheimer's or both? I think the cardiovascular part, I'll give you 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.

1:35:48But 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 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. So EPA antagonizes the arachidonic acid pathway and has like an antithrombotic effect, anti-inflammatory effect. And so there was really two reasons to think why omega-3s could lower risk.

1:36:21And one was through the EPA antithrombotic effect. The other is triglyceride lowering. And so what strength was set up to do was really a triglyceride lowering trial. And it didn't work overall. There was a hint of benefit in the secondary prevention arm. 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 reduced trial was, which is the EPA only trial. So the reduced trial showed a benefit and it could have been, likely had some effects of the mineral oil placebo tilting it a little bit.

1:36:53I've heard this explanation before, but say a little bit more about why mineral oil as a placebo could have been harmful. But you'd actually look at the inflammatory signaling and increased inflammation. And so it had some inflammatory, Paul Ritker 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.

1:37:24You take all that away, it still worked. EPA only worked. And then 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? It 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 have been, but in the combined trial, the DHA EPA trial, the placebo was corn oil inert and

1:38:00you're doing apples to apples. 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 reduces, shows a benefit for pure EPA. Now then we had the prominent study, which is a triglyceride-lowering trial with a fibrate, PMO fibrate showed no benefit. It's very similar to the STRENGTH trial population. What that says is that EPA does work on reducing events.

1:38:31But not through triglyceride-lowering? Not for triglyceride-lowering. It's more for the antithrombotic, 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've had the same you've seen here, and he's talked a lot about, but 8.4 people, one of the other things is they don't get as much DHA to the brain.

1:39:02They 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 Lysophosphosidylcholine form of DHA. That's the preferred substrate for DHA to cross the blood-brain barrier. And so now for the first time, you can now get Lysopc-DHA, it's coming, it's on the horizon.

1:39:37And so we're actually, as part of Jocasta, we're going to be doing studies with Lysopc-DHA on showing getting across the blood-brain barrier. Completely independent of the cloth at work. Right, exactly, yeah. That's coming. And 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. Most of your DHA 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.

1:40:08I 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

1:40:42to get the DHA in the brain? So you have to get the Lysopc form to get to the brain. You have very limited capacity to convert that into the Lysopc form. Oh yeah, absent another... Yeah, so you have to make this Lysopc form, which you can do with either a fish-based oil or a krill-based oil. You can make Lysopc DHA. So that's the next hopeful excitement around the DHA and brain health that I think needs to be further evaluated. But there is no version of that on the market today. It's coming, it's coming, yeah.

1:41:12Yeah, 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 for 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.

Clinical trials and drug development

1:41:27You've been involved in so many clinical trials over the course of your life, and there's so much discussion about AI and 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 than 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

1:42:01course 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, I 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

1:42:32trials based on using AI? 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

1:43:02for 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 2, what percentage of the patients enrolled in those trials do you believe were nearly 100% compliant? We actually, there's what's called on-treatment analysis or kind of looking at PK, you know, who has the right, taking the right drug. It always 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?

1:43:36You 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. 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 to 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

1:44:09harder 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

1:44:41and 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 looks like all LDL lowering drugs, even PCSK9s, have a little bit of a diabetes signal, except for obocetrapin. I mean, just the opposite. This 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?

1:45:11Right. 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, I'm not sure what the drug matching for a gene would be, but it's not that often. If you can't, the 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,

1:45:47which 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 winding 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? Or there are any familial 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

1:46:18that much anymore once azetamide came into play because it's pretty much the same as azetamide, but azetamide is a lot easier to take. And does azetamide 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 PSK9 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 could be a mechanism. But there's

1:46:52been 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 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, you know, 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 6%? Why not go at a lower dose and lower risk? What's more about how do you mitigate the risk? No,

1:47:25the MA, it is, 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 it 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,

1:48:00understand 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 very much in favor of taking the

Biotech investing landscape

1:48:22statin. How many other C-TEP inhibitors are in the pipeline at the moment? To our knowledge, no others. We're it. If we're successful, there are going to be a lot more, but it's very hard to beat ovocetripib. 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, a Japanese company first discovered it. It was sold to Amgen. 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 C-TEP inhibitors and then they sort of

1:48:55abandoned it? Well, they wanted to make a better C-TEP 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 ovocetripib has from a pharmacokinetic perspective. And to give folks, again, just the 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?

1:49:26It's well over a billion, but this started 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 three to $4 billion to approval. That accounts for the failures too, but it might be even more if you count 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.

1:49:58What 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

1:50:31biotech 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 4% per year,

1:51:04which is pretty minuscule growth, they got to add a lot of new products to their pipeline. And 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,

1:51:36but even drug discovery. China, for example, has just become a huge investment in, for every chemist in the United States, just by 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 an opportunity. I mean, I still think we have the science and the innovation, and we have the creativity that could lead the world and coming up with the new ideas. But China

1:52:06is going to be able to have us be able to take it to the next level, 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,

1:52:39but we continue to have a high benefit to risk ratio too. I mean, so we have to see how that plays

Closing thoughts and disclosures

1:52:45out. 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 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

1:53:17talk 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 want to, I don't like to talk about things that I'm directly involved in as well. Right, 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

1:53:51a primate study and showed great data. And the primates got published in Nature, you know, 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, but 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 to decide to do was we basically,

1:54:26we have to sort of 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 know the MOA. We do think that the latest is that the full length, yeah, the full length Clotho doesn't likely cross the blood-brain barrier, but

1:54:56there's 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. That would be great. We can talk about the benefits of Clotho. Yeah, it is. It's very high risk, but I know so many of obviously the investors in Jocasta

1:55:27and 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. Right, right. 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

1:56:01we 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

1:56:34lipids. 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, you know, 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

1:57:09weren'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 clotho, I'm pulling for obocetrapib. 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

1:57:44you can go after complicated diseases from multiple vantage points. It's clear we're going to need multiple therapies. That's the thing. Obocetrapib 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 about you. Yeah, so much fun, Peter. Thank you. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com forward slash show notes. If you want to dig deeper

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