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

View the Show Notes Page for This Episode https://peterattiamd.com/michaeldavidson/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260914-pod-michaeldavidson&utm_content=260914-pod-michaeldavidson-podfeed Become a Member to Receive Exclusive Content https://peterattiamd.com/subscribe/?utm_source=podcast-feed&michaeldavidson%20=referral&utm_campaign=260914-pod-michaeldavidson&utm_content=260914-pod-michaeldavidson-podfeed Sign Up to Receive Peter's Weekly Newsletter https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260914-pod-michaeldavidson&utm_content=260914-pod-michaeldavidson-podfeed Michael Davidson is a world-renowned cardiologist, lipidologist, and the founding CEO of NewAmsterdam Pharma. He begins this episode by sharing how his family history shaped his interest in lipidology and primary prevention. He explains why prevention should focus on causal drivers of disease rather than near-term risk and examines the causal relationship between LDL and atherosclerotic cardiovascular disease. Michael then traces the complicated history of CETP inhibitors—from the original rationale that raising HDL would reduce cardiovascular risk to the failures of torcetrapib, dalcetrapib, and evacetrapib—and explains how lessons from these trials ultimately led to the development of obicetrapib. He reviews the phase 2 and phase 3 trials of obicetrapib, its effects on LDL-C, apoB, LDL particle number, and Lp(a), the ongoing cardiovascular outcomes trial, and where the drug could fit alongside statins and other lipid-lowering therapies. Peter and Michael discuss the relationship between statins and diabetes risk, then turn to the potential role of obicetrapib in Alzheimer's disease prevention, exploring the genetics of APOE4 and CETP, cholesterol metabolism within the brain, and emerging biomarker data. Finally, Peter and Michael explore the benefits of omega-3 fatty acids and the challenge of delivering DHA to the brain, as well as ongoing work on klotho in preparation for clinical trials. They discuss the potential for AI to transform clinical trials and the scientific and financial challenges of developing new therapies for cardiovascular and neurodegenerative disease. We discuss: Michael's path to lipidology, and his passion for primary prevention [3:30]; Reframing prevention around causal drivers rather than time horizon [9:30]; What CETP inhibition does, the evolutionary biology of CETP, the HDL-raising rationale, and Pfizer's torcetrapib failure [15:00]; Why raising HDL is thought to be beneficial, a quick review of the functions of HDL, and how this connects to torcetrapib [24:00]; The graveyard of CETP inhibitors: Roche's dalcetrapib, Lilly's evacetrapib, and Merck's REVEAL trial [27:15]; The causality of LDL in cardiovascular disease [34:30]; Reviving obicetrapib at NewAmsterdam, and confirming the benefit is LDL lowering: the TULIP data, the abandoned statin-intolerance path, and the Mendelian randomization verdict on HDL [37:30]; Phase 2 and phase 3 trials of obicetrapib—ROSE, BROOKLYN, BROADWAY, and TANDEM—and the PREVAIL outcomes trial, with the European and US approval paths [44:45]; Discordance among LDL-C, LDL-P, and apoB with CETP inhibition, and obicetrapib's Lp(a)-lowering effect [50:30]; Where obicetrapib fits in the lipid-lowering toolkit, the case against high-dose statins, and the problem of drug pricing [57:30]; The case for obicetrapib in Alzheimer's: the APOE4 and CETP genetics, the animal models, and funding Alzheimer's research [1:03:45]; Brain cholesterol metabolism and the APOE4 mechanism: the blood-brain barrier, astrocyte cholesterol efflux, the amyloid-tau cascade, the role of HDL, and why statins don't cause Alzheimer's disease [1:08:00]; The biomarker evidence: the CSF pilot study, Alzheimer's as a disease of middle age, the pharma graveyard problem, and the p-tau 217 results from BROADWAY [1:17:45]; Whether obicetrapib translates into clinical benefit for Alzheimer's disease: the risk of fooling yourself, the persistence of the amyloid dogma, ARIA in APOE4 homozygotes, and the next prevention trial [1:28:00]; Fish oil, EPA, and DHA: the cardiovascular trials and the challenge of delivering DHA to the brain [1:32:00]; Two open problems: using AI to reform clinical trials, and the statin–diabetes signal [1:41:15]; What it takes to develop a drug, the biotech investment landscape, and the klotho program [1:48:15]; Closing reflections: what to do if you carry APOE4, balancing motivation against over-testing, and the need for multiple therapies [1:55:15]; and More. Connect With Peter on Twitter https://twitter.com/PeterAttiaMD, Instagram https://www.instagram.com/peterattiamd/, Facebook https://www.facebook.com/peterattiamd/ and YouTube https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:11Dr. Peter Attia?

  Hey, everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive, member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription.

• 0:54Dr. Peter Attia?

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• 1:04Dr. Peter Attia?

  My guest this week is Michael Davidson. Michael is a cardiologist, lipidologist, and the founding CEO of New Amsterdam Pharma. He is a recognized leader in lipidology, having coordinated more than 1,000 clinical trials, published over 350 peer-reviewed papers, and authored three books on lipid disorders and cardiovascular prevention. His work spans statins, novel lipid lowering therapies, omega-3 fatty acids, and cardiovascular drug development. He also founded several biotech companies and clinical research organizations, including the Chicago Center for Clinical Research, Omthera Pharmaceuticals, and Corvidia Therapeutics. Michael also previously served as the president of the National Lipid Association.

• 1:49Dr. Peter Attia?

  Michael's career has spanned the intersection of lipid science, prevention, and drug development. And with obacetropib, he is now at the center of one of the most important open questions in cardiology: whether CTEP inhibition can finally deliver meaningful reductions in LDL, ApoB, LP-LA, 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 obacetropib different, obacetropib's effect on LDL cholesterol, ApoB, LDL particle member, LP-LA, diabetes

• 2:34Dr. Peter Attia?

  risk, and cardiovascular outcomes, how obacetropib may fit alongside statins, ezetimibe, PCSK9 inhibitors, and other lipid lowering therapies, the complicated biology of HDL, brain cholesterol metabolism, APOE4, and the potential role for obacetropib 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.

• 3:13Dr. Peter Attia?

  Michael, thank you so much for coming out. It is hard to believe that this is our first meeting in person, given how many years we've worked together electronically and in other ways.

• 3:23Speaker 01

  Right. Yes, great to be here, Peter.

• 3:25Dr. Peter Attia?

  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.

• 3:37Speaker 01

  I'm a cardiologist, lipidologist. I run the lipid clinic at University of Chicago. I'm a professor. I see patients actually four full days a month, and that's a pretty loaded, prevention-focused practice.

• 3:51Dr. Peter Attia?

  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?

• 4:06Speaker 01

  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 got very interested in lipids in medical school. So I did the original Niasson trials that went back into the 80s, late 70s, actually. And then after training residency, I started doing research in 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 all the statin trials. It's been my passion is to be involved in clinical trials. And as a cardiologist, did the usual stuff that cardiologists do, and then focused primarily on prevention. So I opened a prevention

• 4:50Speaker 01

  center out of my fellowship, along with a research company that did all the clinical trials, and that's been my path ever since. And then the biotech startups started happening about 15 years ago.

• 5:02Dr. Peter Attia?

  We have some overlap in some of those companies, one of which we'll talk about. But maybe even before we get into some of the really exciting things going on in pharma, maybe we can just speak a little broadly about prevention, because there really isn't, at least as I see it, a uniform consensus around how aggressively one should be trying to prevent ASCVD. Sometimes I feel like people look at me as though I have multiple heads when I talk about taking steps towards prevention in 30-year-olds, for example, because by any calculable metric, their 10-year risk is very low and would not necessarily justify the steps we might take. But you're more thoughtful, you're more astute when it comes to all these things. I'd like to hear your point of view and how you think

• 5:46Dr. Peter Attia?

  about primary prevention, and we can differentiate that from secondary later on.

• 5:50Speaker 01

  It always is a hard sell to get a 30-year-old to start taking a statin, for example. And so I explain the primordial prevention concept, which is basically, you want to stop plaque from forming before it's there. It's a lot easier to stop it from forming than it is to reversing it when it already exists. We have this path, and right now, today, which is the mainstream, is that you wait till someone has significant plaque buildup, or even a heart attack or a stroke, then you treat super aggressively to get the LDL down. But we know from genomics that if you have a low LDL throughout your whole lifetime, it prevents heart disease in a much greater degree. For example, I mean, if you lower

• 6:34Speaker 01

  LDL before you have a heart attack, it's very effective. If you have a heart attack and you lower LDL, it still has benefit. But once you have heart failure, there's no benefit to lowering LDL. And so the earlier you start, the better. What I like is the 8-gram rule, which is that 8 grams of cholesterol in your lifetime lead to heart disease. So that is 200 milligrams per deciliter times 40 years is 8 grams, or 100 milligrams per deciliter times 80 years is 8 grams, or 80 milligrams per deciliter times 100 years is 8 grams. So you can think about it in that sense, that the data says that if you keep your LDL below 80 throughout your lifetime, you don't get heart disease. So I think you

• 7:15Speaker 01

  said this as well. I mean, we have the knowledge to prevent heart disease now. It's applying it earlier in life that really makes the difference. That's my pitch to the 30-year-old. And there's a lot of pushback, and I try to then, if necessary, provide more information to them, which is, we can do genetic testing, we can do polygenic risk scores. If they're old enough, we can do coronary calcium scanning or more advanced plaque analysis. We can look at other risk factors like LP-LA 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

• 7:58Speaker 01

  motivators, but it's not always the case.

• 8:01Dr. Peter Attia?

  It certainly was in you. I've shared my story about how rampant heart disease is in my family and how it was sort of my foray into even thinking about all of these cardiometabolic diseases. Your story, by the way, is just incredible in that it's identical to that of my father-in-law. My father-in-law's father, whatever, my wife's grandfather, also died at 47 in the hands of his 16-year-old son.

• 8:26Speaker 01

  So my brother had bypass 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. My brother, who's also a family doctor, went on and to become a vegetarian, really strict diet, did not take statins until much later. Then 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,

• 9:09Speaker 01

  one starts statin later. And so that decade, the 30 to 40 decade, and even maybe 20 to 30, such an important timeframe, when the plaque itself is starting to form relatively rapidly. And that's when you want to have your most effective treatment there to prevent it. And that's why I become an advocate for earlier in life, the better when it comes to the statin there. Now with women, we have to be careful about the whole pregnancy issue and stuff like that. And we also still balance that as well. But it's really upcoming that type of information. I know people bring up relative risk, absolute risk, 10 year risk. We're talking about more about preventing heart disease when you're 80 or 90, not 10 years from now.

• 9:49Dr. Peter Attia?

  Yeah, I guess the other point that for me was a really wonderful way to think about it that I would credit to Alan Snyderman, who wrote a paper, I feel like it was about 12 years ago, but he, at least for me, was the first time somebody repositioned the argument of rather than talk about treating five year risk, 10 year risk, 15 year risk, or trying to stretch that out, reframe it as we treat causal drivers of disease. And if that's the case, then the discussion changes entirely. And people who listen to this podcast have probably heard me use the analogy, but it's why we target smoking cessation so aggressively. It's not that everyone who smokes gets cancer, and it's not that everyone who gets cancer

• 10:31Dr. Peter Attia?

  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 till you hit 15 or 20 pack years that your risk really steps up. But there's not a single doctor on the planet that I would imagine saying, listen, Michael, I know you've been smoking a pack a day for a year. Keep it up for another 10 years, 15, 20 at the

• 11:13Dr. Peter Attia?

  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 the time horizon.

• 11:42Speaker 01

  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

• 11:51Dr. Peter Attia?

  That's right.

• 11:51Speaker 01

  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 it. But it is causal and we know that. So why not treat it early as you can in life? And I think that's what we advocate for. We're not always successful, but I think we get the message across. And like I said, we have the tools now, if we just apply them much more effectively.

• 12:15Dr. Peter Attia?

  Why do you think that? I mean, not that we should waste too much time speculating, but I don't have a great answer for it. So I don't understand why we understand that nobody should be walking around with untreated hypertension, even if they're young and even if they're asymptomatic, because most young people with hypertension would be asymptomatic. And you could argue, well, is the anti LDL issue really all about drugs? Is it that people view it as sort of a pharma conspiracy or something like that? I mean, what is your take on why this one issue around LDL has become so contentious?

• 12:51Speaker 01

  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 genetics, there's nothing they can do about other, and 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's not a, it is about the statin, but we try to find other ways to get the LDL down if necessary.

• 13:36Speaker 01

  But I wish there was more. Another problem we have, of course, is the primary prevention guidelines, like American Heart, are not very effective. They don't really emphasize as much as like you and I, if we were writing the guidelines, we'd have a very different approach to how we manage elevated LDL. We would be advocating a much earlier intervention in life. We just don't have those guidelines that are there to help get physicians on board as well.

• 14:01Dr. Peter Attia?

  It's interesting about the lifestyle point, because ironically, lifestyle has a far larger impact on managing high blood pressure, where weight loss and exercise, individually and collectively, have a greater impact on hypertension, which still means there are a lot of people out there, by the way, who don't respond, as you know, fully to those interventions and can be exercising of normal weight and still have essential hypertension and require medication. But I still don't see the reluctance or resistance to it, the same way I do with managing dyslipidemia. So I don't know. I don't have any great insight into it, but it does make me sad for people who become ultimate victims of it.

• 14:38Speaker 01

  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 obacetropib, that might be the last mechanism. And once that study prevails, the prevail trial, we have a 10th different mechanism of action of LDL lowering and benefit. And I think hopefully, all the obstacles will go away and people say, let's just start treating LDL as early in life as feasible.

• 15:12Dr. Peter Attia?

  Let's talk a little bit about obacetropib. Your colleague, John Kaislerlin, was a guest on this podcast, gosh, I want to say three, maybe four years ago. Certainly one of the more enjoyable discussions I've had, because I tend to really enjoy talking about these things. But I think it would be a fair assumption that many people listening to us now have either not heard that podcast, and if they did hear it, do not remember the ins and outs of CTEP inhibition. So let's assume that we're starting from scratch. Let's talk about this totally new class of drugs. Let's also just acknowledge, as a disclosure, you are currently the CEO of a company called New Amsterdam Pharmaceuticals, which is the manufacturer of a particular drug we're going to talk about in this class. So take us back

• 15:57Dr. Peter Attia?

  to, well, I don't know when the drug entered clinical trials, but I know when it ended, which would have been about 2006?

• 16:05Speaker 01

  I think it was eight.

• 16:07Dr. Peter Attia?

  Okay.

• 16:07Speaker 01

  On trisepip.

• 16:08Dr. Peter Attia?

  Yeah.

• 16:08Speaker 01

  It could have been 2006.

• 16:09Dr. Peter Attia?

  I think, I feel like it was the fall of '06, but anyway.

• 16:11Speaker 01

  You're right. It was definitely Christmas, December, got the call, somewhere in that range. Yeah. So it's

• 16:17Dr. Peter Attia?

  All right. So first, this was Pfizer

• 16:19Speaker 01

  Pfizer.

• 16:20Dr. Peter Attia?

  combining this with

• 16:21Speaker 01

  A torbostatin.

• 16:22Dr. Peter Attia?

  a clinical trial. Okay. Go back from that a decade into the discovery of yet another mechanism, because you've already alluded to this, which is lowering LDL is the goal, but there are many paths to get there. Statins have taken one path, which is we're going to inhibit cholesterol synthesis. The liver will overcompensate by trying to pull more LDL into the liver, and that will lower LDL. We're going to come and talk, I want to come back and talk about bile acid sequesterants. We probably won't get to azetimibe. We might mention PCSK inhibitors. CTEP inhibitors are totally different. So just explain what they do.

• 16:54Speaker 01

  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, the dog, they have very low LDLs, very high HDLs. They don't get apathosclerosis unless you give the rat or the mouse CTP trans genetically. Then they get high LDL, low HDL, and they get apathosclerosis. Like the dog, don't get

• 17:35Speaker 01

  apathosclerosis. 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 apathostrophic animal models is to give the mouse CTP. And that's what we use in a lot of our studies to show that you can induce apathosclerosis and a different therapy can reduce apathosclerosis. So it's very much a modulator of the LDL HDL levels in mammals.

• 18:05Dr. Peter Attia?

  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?

• 18:17Speaker 01

  It's conservatory. In other words, you didn't have, chasing the woolly mammoth, you didn't have a lot of cholesterol available to you in the diet.

• 18:25Dr. Peter Attia?

  But why wouldn't dogs have the same issue then?

• 18:27Speaker 01

  They have plenty of meat. All they eat is meat and all that kind of stuff. They had plenty of cholesterol.

• 18:32Dr. Peter Attia?

  So we think it was truly just a scarcity issue?

• 18:34Speaker 01

  Yeah, scarcity.

• 18:35Dr. Peter Attia?

  So animals that had more scarce nutrients would want to hyper conserve cholesterol?

• 18:41Speaker 01

  Right. I mean, almost all, let's say vegetarian animals don't have CTP. So you know, if you look at it from that perspective, you know, we're meant to be a vegetarian, maybe. So that's how you think about how CTP plays a role in lipid homeostasis. But it's a conservatory mechanism. If you can't get a lot of cholesterol available from the diet, it's just a way of conserving cholesterol in the body. So when you block 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.

• 19:23Speaker 01

  We had data from the Framingham Heart Study, that if your HDL was high, you're protected from heart disease. They used the ratio total cholesterol to body to 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 of 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.

• 19:53Dr. Peter Attia?

  And where were we in our knowledge of niacin's impact on HDL and, and events?

• 19:59Speaker 01

  We only knew niacin alone in the coronary drug project did lower events. We did also knew niacin is one of the drugs that was studied and had a alone, that was the pre-statin era, had a reduction in cardiovascular events.

• 20:13Dr. Peter Attia?

  In secondary prevention?

• 20:15Speaker 01

  Secondary prevention, yes.

• 20:16Dr. Peter Attia?

  And how significant relative to what we see with statins?

• 20:18Speaker 01

  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.

• 20:32Dr. Peter Attia?

  And niacin also raised HDL cholesterol, didn't it?

• 20:35Speaker 01

  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-HI and HPS-THRIVE trial. Both showed niacin on top of statins did not lower LDL, so did not lower.

• 20:50Dr. Peter Attia?

  Events.

• 20:51Speaker 01

  Events. The THRIVE HPS2 trial there was, it looked like if you looked at it in another way to look at the analysis, it did lower events by LDL lowering because it lowers LDL also. That was actually post torcetropib. So torcetropib was the Pfizer CTP inhibitor. Everyone was rushing to get a CTP inhibitor because it raised HDL 50, 75%. We thought we'd have the cure for heart disease. Every 1% increase in HDL in these other trials lowered risk by 3%. So you can see the magnitude of the benefit would be quite substantive if you can raise HDL. I personally had a low HDL in the McPhamley, 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.

• 21:35Speaker 01

  1993 was the patent was issued. I had a lot of hope that CTP inhibition would be the end of heart disease. So 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.

• 22:06Dr. Peter Attia?

  And do you think that that was attributed solely to the increase in blood pressure?

• 22:11Speaker 01

  The blood pressure increase actually was, was only the tip of the iceberg. The drug had a very prominent effect on increasing, getting to the adrenal glands. And when marked the 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 give torcetropib and the blood pressure would go up dramatically within an hour without, and that's no, they have no CTP. The rat has no CTP. So that said, it's not, it's an off-target effect. And since then, there's been a lot of CTP inhibitors that have, let's say four.

• 22:47Dr. Peter Attia?

  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?

• 23:07Speaker 01

  No, Roche, Dalsetor.

• 23:09Dr. Peter Attia?

  Okay.

• 23:10Speaker 01

  It was mostly off-target. It was, obviously there were some that thought, okay, maybe the target's off, but that came later, more validation of the target actually came later as well, that it is a valid target. I can get into that, but the initial thinking was it could be well, an off-target effect. And Pfizer did a lot of work on understanding that. Others that followed can actually isolate the off-target effect to a certain composition in the molecule itself. I mean, they knew that the chain around 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 developed other CTP inhibitors that lacked 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.

• 23:55Speaker 01

  No one's thinking about it for LDL lowering. That's a key thing.

• 23:58Dr. Peter Attia?

  What was the thinking, Michael? So aside from the fact that epidemiologically, we could observe that people with high HDL, low triglycerides and low LDL did better. Was there any sense of mechanistically, why would raising HDL do something? In other words, how was causality established as opposed to association?

• 24:22Speaker 01

  That's a great question, but there is a lot of work that went into the HDL function. What does HDL do? So HDL is a lipoprotein that is also made by the liver and the intestines and it goes to different organs and it basically picks up cholesterol. It effluxes cholesterol into the lipoprotein. It goes from an empty garbage truck to a loaded garbage truck, an empty peat-a-pocket to a spherical, how you want to describe it. And matures, it goes from this pancake up to a big ball filled with cholesterol. And there's different enzymes along the way that kind of help maturation the particle. And once the spherical particle is mature, it goes to the liver and gets cleared.

• 25:04Speaker 01

  And actually, the predominant route, most people don't realize this, but the majority of bile that the liver makes comes from HDL. It comes from HDL. That's the bile. It goes funnel more into the biliary system and then out into the intestines. So HDL is the precursor, but it has a lot of functions that are really interesting. It picks up a lot of garbage along the way. It picks up all these inflammatory components, the cytokines, and it's like a dump truck. It's picking up stuff and it takes it back to the liver for clearance. That's what the purpose of it is. And part of that is cholesterol. And so people thought it's going to the plaque, it's picking up cholesterol. We call it reverse cholesterol transport. And it picks up the cholesterol and removes it from the plaque. And that's why you get less heart disease with HDL.

• 25:49Speaker 01

  So it was all mechanistically based on that finding. Even though the amount of cholesterol that it got from the plaque was actually miniscule compared to what it does to other organs, but it's the vehicle for cholesterol transport. And it also has other functions. It's very important in immune function and trying to battle innate pathogens and things like that. It has a lot of other important roles to play in human health. But that was the reason why we thought HDL being high was good. And then it functioned by removing cholesterol from the artery wall and taking it back to the liver for clearance. Learned it's a lot more complicated than that, but that was our thinking back in 2006 when torcetropib unfortunately kind of failed.

• 26:32Speaker 01

  And just to be honest where I was, I mean, I was a big fan of torcetropib 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 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.

• 26:56Dr. Peter Attia?

  How much did HDL go up with torcetropib?

• 26:58Speaker 01

  About 75%.

• 26:59Dr. Peter Attia?

  Wow. So despite that, that really tells you the off-target effects were devastating.

• 27:04Speaker 01

  Right, yes.

• 27:05Dr. Peter Attia?

  Did it have an effect on LDL very much? I don't remember.

• 27:07Speaker 01

  About 15%, at most, maybe 10 to 15%. It was really not even something people even paid attention to, the LDL effect.

• 27:16Dr. Peter Attia?

  Okay, so then the Roche compound comes along. What was the story with that trial?

• 27:20Speaker 01

  So it's a weak CTP inhibitor and they even called it a CTE modulator, a very safe drug. And it raised HDL 30%, maybe 40 in some trials. So not a much weaker HDL raising effect, no 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.

• 27:53Dr. Peter Attia?

  Major adverse cardiac events.

• 27:54Speaker 01

  Right, right. Heart attack or stroke reduction was nothing. There was no benefit there, not even a trend. It was just completely flat, but very safe. And so that was the second failure, high-profile failure. Actually went to another trial later, it's still neutral, no benefit on major adverse cardiac events. That's number two.

• 28:14Dr. Peter Attia?

  And then Merck?

• 28:15Speaker 01

  Then Lilly.

• 28:16Dr. Peter Attia?

  Oh my gosh.

• 28:16Speaker 01

  Then Lilly, which was evacetropib. 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 was trying to go fast because again, this could be a huge opportunity to reduce heart disease. So it was all about, 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.

• 29:01Dr. Peter Attia?

  In secondary prevention?

• 29:02Speaker 01

  Secondary prevention. It was a high-risk secondary prevention.

• 29:05Dr. Peter Attia?

  By the way, Michael, the first two studies were primary or secondary?

• 29:08Speaker 01

  All secondary.

• 29:09Dr. Peter Attia?

  All secondary.

• 29:09Speaker 01

  These are all secondary prevention, yeah. What's important about that trial is azetimibe, which is now a well-known, we use azetimibe all the time, Zetia, for lowering LDL. They also did an ACF, acute coronary syndrome trial, which was similar to what was done in the ACCELERATE trial, which is the Lilly trial. We know that two years is too short because in a similar trial with azetimibe, which is a well-proven LDL lowering drug, it has, everyone recognizes the benefit of azetimibe. 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 ibocetropib in the ACCELERATE trial.

• 29:52Dr. Peter Attia?

  Although with Repatha and Praluent, we did see benefit at about two years.

• 29:57Speaker 01

  This was only a 15% LDL lowering.

• 29:59Dr. Peter Attia?

  Yeah, yeah, yeah, yeah.

• 30:00Speaker 01

  So it's also interesting, in the ODYSSEY outcome study, which is the Praluent, which is the other PCSK inhibitor, if you look at populations that had LDLs below 100, which is what this, they also didn't separate until after two years.

• 30:14Dr. Peter Attia?

  Same with Fourier, which one was more heavily?

• 30:16Speaker 01

  No, Fourier was Repatha.

• 30:17Dr. Peter Attia?

  But which one was more heavily statinized? I can't remember.

• 30:20Speaker 01

  They both are pretty, but Fourier was not acute coronary syndrome population.

• 30:23Dr. Peter Attia?

  Got it.

• 30:24Speaker 01

  It was a chronic stable. They sent a separate, acute coronary syndrome populations sometimes can be pretty sick and they get a lot of events. And so you have to go longer to see the benefit.

• 30:33Dr. Peter Attia?

  Are you saying that your view is maybe the Lilly study was stopped too soon?

• 30:37Speaker 01

  It was stopped for futility when it should have kept going. That was, for us, a big issue for our drug, obacetropib. That was the hardest one to explain.

• 30:46Dr. Peter Attia?

  And what were the features of the Lilly drug in terms of HDLC and LDLC kinetics?

• 30:52Speaker 01

  It lowered LDL to about 15 to 20%.

• 30:55Dr. Peter Attia?

  And raised HDLC.

• 30:56Speaker 01

  HDL, again, 75% or so. It's a good, and 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.

• 31:10Dr. Peter Attia?

  That's interesting. It had an overall all-cause mortality benefit?

• 31:13Speaker 01

  Right.

• 31:13Dr. Peter Attia?

  What other causes was that attributed to?

• 31:15Speaker 01

  Well, it was largely cardiovascular, but it has some non-cardiovascular mortality. So cardiovascular mortality was almost significant. There was also some non-cardiovascular benefit as well.

• 31:26Dr. Peter Attia?

  Did they prespecify that they had to have an outcome at two years? Is that why they stopped it?

• 31:30Speaker 01

  They had prespecified that there would be an analysis at two years. There are also corporate issues involved. It was a tough time for Lilly financially. It's very different than where they are today. They had to make some quick decisions about prioritizing their pipeline. As big corporations go, you have to make these decisions. So they had decided to cut the study short. Again, HDL raising, you would think would have a benefit already. So it was the LDL lowering wasn't really thought of as the main mechanism there.

• 31:56Dr. Peter Attia?

  Did that study show any improvement in diabetes?

• 31:59Speaker 01

  It did also, yes. All the CT inhibitors, even torcetropib, showed a diabetes benefit, all of them. So this is again why we're focusing on that with obacetropib as well. So the important study that was the Merck study, that actually saved the class, even though the drug itself didn't make it to market for different reasons. It was, to Merck's credit, I mean, they started the trial, again, all about HDL, but when they saw what happened with the Lilly drug and dalcetropib, 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

• 32:40Speaker 01

  very large study. They went for four years. The baseline LDL was 60. So we're talking about already low LDL. They got a 17% LDL lowering, 11 mg/dL absolute LDL lowering. They got a 9% relative risk reduction, which is what you'd expect, if not more so, 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. And so if you took it, you would not wash the drug out for years,

• 33:23Speaker 01

  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.

• 33:33Dr. Peter Attia?

  And how did they figure that out only in the large Phase III study without knowing it in, say, a Phase II? Like, what was it that even brought that to their attention?

• 33:42Speaker 01

  As the studies went along and they started getting more, in the Phase II studies, they didn't look at long-term clearance of the drug. It started, it was-

• 33:50Dr. Peter Attia?

  They didn't do the PK stuff?

• 33:52Speaker 01

  They did the PK. They knew it was a long half-life. They didn't realize how long. They didn't realize much it got deposited. I did some of them. You actually did fat biopsies to see how much drug was in the fat tissue.

• 34:02Dr. Peter Attia?

  And this was an oral drug?

• 34:03Speaker 01

  Oral drug. Lipophilic, yes.

• 34:06Dr. Peter Attia?

  Wow.

• 34:06Speaker 01

  Yeah. So it was unfortunate in that it was just not a viable commercial drug for that reason, even though it had good safety profile, it lowered MACE. But also because the magnitude of the MACE benefit was modest, people don't realize it's an issue for how you market the drug. But from a proof of concept of proving the drug works to lower LDL and reduce events, it was a great study to confirm that the LDL lowering with a CTV inhibitor can, in fact, result in a cardiovascular benefit.

• 34:35Dr. Peter Attia?

  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 trials, full stop, all of the Mendelian randomizations and all of the epidemiology, and you plot on the x-axis LDLC and on the y-axis event rate, they're all a bunch of lines going down.

• 35:06Speaker 01

  Right, right.

• 35:07Dr. Peter Attia?

  Right? So there are four distinct lines, different slopes, based on different, and therefore, given how tight those regressions are, it becomes very easy to predict what you're getting at. I just want to make sure the listener understands why it is that you're saying, if you have a 17% reduction in LDLC from 60 to 49, you would expect an event reduction on a relative basis of 9%, et cetera.

• 35:33Speaker 01

  Yeah. The formula is easy. It's well-established. For a 1 millimol, which is 38.8 mg/dL of LDL, you get a 22% relative risk reduction.

• 35:46Dr. Peter Attia?

  And that's largely linear.

• 35:47Speaker 01

  It's linear, right. But absolute is the key, not percent. You've got to look at the absolute LDL lowering, and then you can calculate the benefit. 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, 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.

• 36:15Dr. Peter Attia?

  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. It's the genetic lottery that determined your LDL versus mine. The primary and secondary prevention trials are based on a potpourri of drugs. Same with the epidemiologic stuff, which combines both genetic and drugs. So, again, it speaks to this idea that reinforces the causality of LDL, because independent of how it's lowered, you're getting the same effects. You often hear people say things like, well, it's hard to deny that these drugs improve outcomes, but it must be something different than LDL lowering if you want to deny that LDL plays a role. They'll talk

• 36:59Dr. Peter Attia?

  about pleiotrophic effects of these drugs or things like that. But obviously, those arguments become a little bit silly when you consider the totality of the evidence.

• 37:06Speaker 01

  Right, right. I've never been a pleiotropic, in fact, I was the one 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.

• 37:29Dr. Peter Attia?

  So with all of that as background, now let's talk about obacetropib, 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.

• 37:43Speaker 01

  Right. I had sold my previous company an interleukin-6 antibody for heart disease, inflammatory. It's a, I don't know if you've ever heard of IL-6, but it's the key inflammatory cytokine. And that study's actually coming out this year. It's called the Zeus trial. It's a big, big study coming up. So I had sold Corvidia, and John said, let's get obacetropib back from Amgen. Amgen had put it on the shelf because Repatha had struggled on its launch. They de-prioritized 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.

• 38:22Dr. Peter Attia?

  How many years ago was this?

• 38:22Speaker 01

  This is five, almost, this is our sixth year now.

• 38:26Dr. Peter Attia?

  That's so interesting because Repatha launches in 2015.

• 38:30Speaker 01

  Right.

• 38:31Dr. Peter Attia?

  They kept OB on the shelf for five years?

• 38:34Speaker 01

  I think they bought it in 2017. They bought it in 2017.

• 38:38Dr. Peter Attia?

  Interesting.

• 38:39Speaker 01

  They did, actually did a lot of great work on the manufacturing, the process. They worked on the, made it much more cost effective manufacturer, but they didn't do any clinical trials. They just kept it on the shelf.

• 38:49Dr. Peter Attia?

  It already had an IND in the US or this was all?

• 38:52Speaker 01

  They already had phase two data.

• 38:53Dr. Peter Attia?

  In the US?

• 38:54Speaker 01

  In the US, yeah.

• 38:55Dr. Peter Attia?

  Okay.

• 38:55Speaker 01

  It was ready to go. So we initially thought about stat intolerance and using it for those patients as a quick route to the market, but we realized the FDA view on CD inhibition because of the history. We really didn't have a path there. The FDA does not like stat intolerance as an indication. They're very wary of it even really being a true thing, but believe it or not. I mean, you and I see it, we all see it, but

• 39:20Dr. Peter Attia?

  Sure.

• 39:21Speaker 01

  in the academic world and in the FDA, they don't really believe it as a true phenomenon. Because when you look at the placebo controlled trials, it's, you know, very low rates.

• 39:29Dr. Peter Attia?

  About 4.9%.

• 39:30Speaker 01

  Yeah, but even true stat intolerance is very hard to find. I mean, it's in the trials. But anyway, it exists. It exists. That was our first path. However, once we met with the FDA and realized we need to go into a full boat LDL lowering path, which is a much more larger program. And also we know we had an outcome study at the time of the launch of the drug because of the history.

• 39:53Dr. Peter Attia?

  But what were the phase two data that you had at the time of acquisition?

• 39:57Speaker 01

  We had a tulip study, which was the, sort of John had led in a predecessor company.

• 40:01Dr. Peter Attia?

  Yeah. Can you remind me and the listeners what that study looked at?

• 40:04Speaker 01

  So it showed that 45% LDL lowering.

• 40:06Dr. Peter Attia?

  Okay. So what was different about OB?

• 40:08Speaker 01

  It's a much more potent, so it's only, the other CTP inhibitors are all in the 100 milligram plus range. And they lowered LDL, as I mentioned.

• 40:18Dr. Peter Attia?

  And you're at 10 milligrams?

• 40:19Speaker 01

  You're at 10 milligrams, even five milligrams we had initially to lower LDL in that 40 to 45 to 50% range in the trials.

• 40:27Dr. Peter Attia?

  And the HDL raising?

• 40:29Speaker 01

  150%. So it's a lot more effective on both lowering LDL and raising HDL. It was just a much more potent CTP inhibitor.

• 40:38Dr. Peter Attia?

  And the duration of the tulip study was how long?

• 40:40Speaker 01

  It was just a short term study. I think it was eight to 12 weeks, something like that. It was relatively short study. It was very effective, very well tolerated. It was a really nice LDL benefit. So we wanted to look at for LDL lowering. Again, in the meantime, all the mandelina minimization studies, besides the Merck data, at the same time, or roughly the same time, all the mandelina minimization study confirmed that LDL lowering translates into cardiovascular benefit.

• 41:05Dr. Peter Attia?

  Weren't these the same studies, sorry to interrupt, Michael, that suggested that the HDL raising had nothing to do with the benefit of CTP inhibition?

• 41:12Speaker 01

  Right, exactly. Yeah. 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.

• 41:34Dr. Peter Attia?

  This was a paper in Nature circa, what, 2012-ish?

• 41:39Speaker 01

  Yeah, right, exactly. Yeah, that was about, so that was the other important.

• 41:43Dr. Peter Attia?

  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.

• 42:07Speaker 01

  You notice I've really worked hard to avoid saying the term good cholesterol. I'm avoiding using that term because our mutual friend hates it, as we know, but it's the wrong way to phrase it.

• 42:17Dr. Peter Attia?

  Yeah.

• 42:18Speaker 01

  It's the wrong way to phrase it.

• 42:19Dr. Peter Attia?

  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 HDLC 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?

• 42:43Speaker 01

  So HDL is really interesting. We believe it could still have some cardiovascular benefits if you raise it the right way. And also, because HDL's, 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 and how we think about how to advise them about what it means, because sometimes it could be quite good.

• 43:19Dr. Peter Attia?

  I have a friend with very high HDL cholesterol, about 100 milligrams per deciliter and modest LDL cholesterol. So maybe also 100, 110 milligrams per deciliter. And he had always assumed he was totally risk free. Maybe his LDL was even lower than that. It might've been 90 to 100 with HDLC of 100, 110. And I was able to convince him, I said, you know, look, you're right statistically speaking, your HDL cholesterol is probably reflective of something good or protective. But I've read enough cases in the literature to see that we could be looking at highly dysfunctional HDLC. So would you mind getting a CT angiogram? Which he did and he had significant burden of disease.

• 44:02Speaker 01

  Yeah. So he probably, he probably has the SRB1. That's an 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. And there's endothelipase, there's like three HDL raising genes that either don't protect or increase risk. And then you have alcohol. So you throw that in the mix, you get a very complicated story about HDL being high, being protective. The reasons to believe, we still have hope that 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.

• 44:43Speaker 01

  That's what we hope is linked to the HDL raising benefit. We're investigating that now in our, in all our studies.

• 44:49Dr. Peter Attia?

  So when John was on the podcast, again, I think it was four years ago-ish, but a lot has happened since then. So let's talk about where we are today. What is the state of understanding of 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?

• 45:22Speaker 01

  Well, no, Broadway, Brooklyn, Tandem, yeah. So we've now done two more phase two trials and three very large phase three trials. And they're all been completed and were actually filed in Europe for approval. And the US were waiting to time it on the outcome study called, so it started to 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 able to knock on wood, even though we'd have the money to finish the trials, start the trials, get them completed, and then we raise money along the way. Now we have plenty of cash to finish the trial, the prevail trial. So we feel it really worked out well for us because the success of the phase three trials allowed us to fund the finishing of the other trials.

• 46:04Speaker 01

  So timed it extremely well for our efforts. We had ROSE and ROSE II, both showed, again, the 45 to 50% monotherapy benefit. And then in combination with azetimibe, 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 is autosomal dominant genetic disorder, very high LDL, showed a 40% LDL lowering over a year. So it's a one year study.

• 46:36Dr. Peter Attia?

  Tell me about those patients. They were already on?

• 46:38Speaker 01

  Almost all were on high intensity stans. Many were on azetimibe or PCSK inhibitors already. These were very well treated, but their LDLs were still too high.

• 46:47Dr. Peter Attia?

  How high?

• 46:47Speaker 01

  Well, the average LDL is roughly around 100, something like that.

• 46:51Dr. Peter Attia?

  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.

• 46:59Speaker 01

  Right.

• 47:00Dr. Peter Attia?

  So on the familial hypercholesterolemia patients, when you show up at a LDL-C of 100 on whatever combination you're on, obacetropib lowered it by an additional 40%. So lowered it from 100 to 60 milligrams per deciliter on average.

• 47:15Speaker 01

  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 stans, majority on high intensity stans, like 70% were on 20 or 40 of resuvastatin or 40 or 80 of atorvastatin. They're all very well treated. And we got roughly around a 35% LDL lowering benefit. And then adjusting for placebo, a little less than that, but it was around that percent change at 12 weeks. And then it continued for 52 weeks. And so that was our two pivotal phase three trials.

• 47:56Speaker 01

  And in combination with azetimibe, we did another trial called Tandem, where the LDL lowering was very much 50%. So we have a combo pill we're developing, the two drugs together. What was important about Broadway, though, that really helped us a lot was we showed in that study 21% reduction in major adverse cardiac events at one year. It was not statistically 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

• 48:38Speaker 01

  because it's almost identical population in prevail, which is 9,500 patients. And it's an ASCVD atherosclerotic cardiovascular disease population. LDL again, in the higher end, that's the key. You have to try to get higher LDL levels, but not being too high where it becomes. You get too much drop into therapies or you get unethical issues. Ethical issues. So these are all on Maxby tolerated stance. That's called prevail. And that study now is approaching. In the year three of the study now.

• 49:07Dr. Peter Attia?

  And this study will read out when?

• 49:10Speaker 01

  We have two factors to stop the trial. One is that we have a minimum follow up of two and a half years. Again, the learnings from the, from the other trials. And the other is also event driven. How many events to power the study appropriately for, for what we call four point mace, which is the heart attack, stroke, cardiovascular coronary death, and then revascularization coronary. So those are the four point mace. So we have that events need to be adequate to stop the trial. So that may take us into a little bit longer than the two and a half year. The two and a half year mark ends this year, at the end of this year for the minimum follow up.

• 49:44Dr. Peter Attia?

  That will be a trial evaluated in both Europe and the United States?

• 49:49Speaker 01

  All over the world. Yeah. China, Japan, everywhere. It's 400 plus sites and it's a global study.

• 49:55Dr. Peter Attia?

  And the outcome of that study, should it be positive, would be approval in Europe and North America for obacetropib in secondary prevention?

• 50:05Speaker 01

  We actually don't need it for approval in Europe.

• 50:07Dr. Peter Attia?

  Why is that?

• 50:08Speaker 01

  Well, it's a different system. They believe in LDL lowering is LDL lowering. So you don't need.

• 50:11Dr. Peter Attia?

  They don't need the outcome trial.

• 50:12Speaker 01

  They don't need the outcome study for approval. The US is different story. Then they have a year to set up their payer mix. So they have the year for the outcome study to kind of come into the payer reimbursement. For US, it's different because you want to line up your reimbursement at launch. And so we want to have the outcome study when we launch. So actually Europe will be first.

• 50:30Dr. Peter Attia?

  I went through the Rose 2 trial the other day. And one of the things that I found interesting was, and we'll link to the study so folks can see it. But the LDLC lowering, there was also an NMR for LDLP lowering. And then there was ApoB. And there was quite a discordance between those. The ApoB lowering, I don't remember, was maybe 16%.

• 50:52Speaker 01

  Right.

• 50:52Dr. Peter Attia?

  But it was much more modest than the others. What do you think accounts for that?

• 50:56Speaker 01

  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 LDLP person for a couple of reasons. One, it's easier to get in our lab.

• 51:08Dr. Peter Attia?

  Really?

• 51:08Speaker 01

  Yeah, easier actually. ApoB is still pretty easy, but.

• 51:11Dr. Peter Attia?

  I mean, I feel like ApoB is the easiest thing to order.

• 51:13Speaker 01

  Yeah, but LDLP, but also LDLP to me is more commonly discordant than ApoB. You can see it more easily because ApoB LDL is 80, ApoB comes back 85. Is that really that kind of thing? Usually would typically have with LDLP of LDL 70, LDL particles 1500. It's very easy to see the discordance a lot easier.

• 51:37Dr. Peter Attia?

  Which assay did you use for NMR? This was the?

• 51:40Speaker 01

  This is the liposience.

• 51:41Dr. Peter Attia?

  Liposience one, which is owned by LabCorp now?

• 51:43Speaker 01

  It's owned by LabCorp, yes.

• 51:45Dr. Peter Attia?

  This is Jim Cromwell's old assay.

• 51:46Speaker 01

  Right, right. Actually, no, we use the, we use the liposience, yes. That was the assay that we used.

• 51:50Dr. Peter Attia?

  Okay. So that is the most reliable one to my knowledge.

• 51:52Speaker 01

  Right, exactly right. And so we're doing a lot of work confirming that. Tom actually published a paper, when LDLP 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 LDLP. And then there's a study done at the C.

• 52:13Dr. Peter Attia?

  Sorry, you said ApoB and LDLP. Did you mean ApoB and LDLC?

• 52:16Speaker 01

  No, LDLP when they're discordant. In other words, when ApoB is not high and LDLP is high, what explains that? What is the reason why you have a normal ApoB and a very high LDLP?

• 52:27Dr. Peter Attia?

  But I don't understand why small particles would explain that discordance because each particle still has one ApoB on it.

• 52:34Speaker 01

  It turns out the mass of ApoB is different by the size, slightly different from each particle. And that we believe is the explanation that we have.

• 52:41Dr. Peter Attia?

  Why is that?

• 52:42Speaker 01

  It's because when you have the smaller surface, the masses is not just the protein. There's also other sugar molecules that attach to that that make the mass of, when you measure them. And so ApoB is a mass assay. The LDLP is the NMR, the nuclear magnet as a resonance. So CTP inhibition is the one example where you get different results. LDLP 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?

• 53:22Dr. Peter Attia?

  That's actually going to be very interesting when you get your outcome data, assuming that the discordance continues between those two biomarkers. Because you'll be able to go back and say, well, we would predict based on this LDLC or LDLP lowering, what the event reduction should have been. But that might be different than what's predicted by the ApoB reduction.

• 53:42Speaker 01

  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, what's called non HDL cholesterol, which is very close to ApoB. It's LDL plus VLDL cholesterol. We go back to the Merck trial, the REVEAL trial, that showed the benefit there was driven, it was really highly correlated with non HDL cholesterol, more so than ApoB.

• 54:06Dr. Peter Attia?

  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.

• 54:15Speaker 01

  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. In discordance, you can get discordance with using non HDL, ApoB or LDLP. I think by and large, it tells you the same thing, by and large.

• 54:32Dr. Peter Attia?

  Yeah, this is a third order term.

• 54:34Speaker 01

  Yeah, yeah. The cheap way is non HDL. Then ApoB and LDLP are a little bit more precise, but another blab test involved. We know that in our ApoB lowering with prevail, we still do okay. We do okay with the outcome benefit that we want to achieve. We even do better if we use non HDL. But of course, what obacetropib has that we're also excited about is the LPLA lowering benefit.

• 54:56Dr. Peter Attia?

  How much was that?

• 54:57Speaker 01

  It's about 50%.

• 54:59Dr. Peter Attia?

  Which is more than a PCSK9 inhibitor.

• 55:01Speaker 01

  Right, right. In the 50 to 150 range. You have to bracket it by the range of LPLA.

• 55:06Dr. Peter Attia?

  What do you think explains that mechanism of action?

• 55:08Speaker 01

  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. It does reduce production of LPLA. We've done an actual assay looking at, it's a study labeling LPLA and seeing that 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, you know, it's, we have a much more potent CTV inhibitor.

• 55:43Dr. Peter Attia?

  And where are we right now with the antisense oligonucleotide that lowers LP little a? That is still in a phase three trial?

• 55:51Speaker 01

  Yeah, it's coming out this year. It's called Horizon. It's a really important study.

• 55:56Dr. Peter Attia?

  Although it was extended.

• 55:57Speaker 01

  It's extended because.

• 55:58Dr. Peter Attia?

  It could have been stopped for futility, right?

• 56:00Speaker 01

  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 our, what we're doing today. I'm sure you hear it too, but 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 matter is you bring the LDL down, you really mitigate risk substantially.

• 56:33Dr. Peter Attia?

  So you think that the issue with that study was their LDLC was so low that you didn't get enough events. So abolishing LP little a with the drug, the ASO, didn't matter.

• 56:47Speaker 01

  No, no, I think it will matter, but we just don't.

• 56:49Dr. Peter Attia?

  Well, it didn't matter in the timeframe that they looked.

• 56:51Speaker 01

  Didn't need to collect enough events. I mean, it could well matter. I mean, it's going to come out, we believe sometime this year, it's 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. There's others that are, look a lot better, that are moving into big trials as well. And so it's in the LPLA era is getting started. I mean, we're getting to another, hopefully, very important causal factor that can be treated aggressively with therapy. And we, we hope obacetropib can be part of that treatment paradigm.

• 57:36Dr. Peter Attia?

  From a purely cardiovascular standpoint, how do you see obesetropib 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?

• 57:53Speaker 01

  I want to say, again, your question is the right way to frame it. We have to have a positive prevail trial and we have to show the benefits of the drug on top of statins. However, when you think about what statins do well and what they don't do so well. So statins lower LDL and they're well tolerated and they reduce cardiovascular events and they're generic and they're very easy to prescribe. That's all the good things. What does statins not do so well? It raises the risk of diabetes slightly. It raises the LPLA and it does not lower small particles very well. It lowers mostly the non-small particles. But does obesetropib do well? It lowers the risk of diabetes based on our Broadway trial data as well as other CTP inhibitors.

• 58:35Speaker 01

  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 to a statin for that reason. Now, we have the combo pill with azetimibe, which puts us in the same range as the PSCK inhibitors or even the upcoming oral PSCK inhibitor.

• 59:09Dr. Peter Attia?

  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 azetimibe. And we see that, honestly, I think we see that far more than it's reported in the literature. So I understand what the guidance says. The guidance says if the AST and the ALT rise by less than 3X, you can ignore it. It's not clinically significant. But that means you're going to be tolerating patients on Crestor and Zetia walking around with AST and ALT of 80.

• 59:50Speaker 01

  Right, right.

• 59:51Dr. Peter Attia?

  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?

• 59:58Speaker 01

  Not really. I kind of feel the same way. I'm a first do no harm kind of guy. I mean, you're bringing up a very big point for me in my clinical practices. I don't like high dose statins. I don't like 80mg of atorvastatin in particular. I don't like 40mg of resubastatin.

• 1:00:13Dr. Peter Attia?

  Have you seen Tom Dayspring put out a beautiful figure? It's one of 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 it's, I'm sure it demonstrates exactly what you're about to say, which is you're getting virtually all the bang for your buck at that lowest dose. And that curve is so concave down that it's almost unjustifiable to be on a statin above 50% of its max dose.

• 1:00:43Speaker 01

  Yeah, it's like the number needed to harm versus the number you need to treat benefit is just not desirable. I try to cut the statin patients, by the way, they don't want high dose stands either. The whole high dose statin guideline paradigm is off. It doesn't work.

• 1:00:57Dr. Peter Attia?

  And in defense of it, look, I want to be charitable to everybody. It made sense 25 years ago because 25 years ago, you didn't have Repatha, you didn't have Praluent, you didn't have azetimibe, you didn't have bempedoic acid. You had nothing. This was your drug.

• 1:01:11Speaker 01

  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 obesetropib 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 azetimibe combo pill. So we believe that with OB alone and OB with azetimibe, 90% of patients are done with their lipid treatment. And so that's how we think for primary care doctors, that's what they're looking for. They're looking for something they can just add to a statin and then they can call it a day.

• 1:01:51Dr. Peter Attia?

  Explain something to me. So if you go and buy branded Zetia today, it's not that expensive. If you go and buy branded Nexlatol, I mean, it's as expensive as an injectable monoclonal antibody.

• 1:02:06Speaker 01

  Yes.

• 1:02:06Dr. Peter Attia?

  So do you, and maybe you don't want to talk about this, but I have to ask. I mean, when you think about how obesetropib will be priced in the United States, is it going to be priced more like Zetia or is it going to be priced more like Nexlatol?

• 1:02:21Speaker 01

  Unfortunately, it's all about access, not about price. That's the big difference. So we haven't decided on price. You don't do that till you launch, but it's really fortunately how the system works. If you price too low, the PBMs don't have any rebating profits to make. So they don't put it on formulary. And so you got to be able to play the rebate game and price it accordingly. We're starting to see that breakdown also with Lilly Direct and all these. We love to see that system get better as time goes on. And so people can just pay a reasonable price out of pocket if they want to, and they get the drug.

• 1:02:58Dr. Peter Attia?

  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.

• 1:03:07Speaker 01

  Well, we know Repatha was a huge example, right?

• 1:03:09Dr. Peter Attia?

  Yeah, I mean, what a blunder to price that drug at $16,000 per year. I mean, they could have run roughshod over the market if they had just priced it within, yeah. So again, assuming that the results of prevail are as promising as they should be. You never know, but what they should be, it would do such a disservice to patients for this drug to be priced even at the level of Nexlatol. Again, Nexlatol is an inaccessible drug. To me, it's a donkey ass drug. $6,000 a year for that drug, it's just not worth it.

• 1:03:42Speaker 01

  That's why we have a hard time finding a place for it for that reason in the clinic. It's really limited the stat intolerant patients that don't want to take injections.

• 1:03:50Dr. Peter Attia?

  And it stinks. It barely works like it's just a weak drug. Now, John predicted we are going to see big effects on metabolic disease. Okay, that was an easy prediction to make based on everything you'd seen before it. But the other prediction he made was even more intriguing to me, which is it might be, and I'm paraphrasing, but something to the effect, it might be that the most impressive thing about this drug is its effect on Alzheimer's disease. So tell me what it is that made you and John feel that way four or five years ago? And have you been validated in your predictions?

• 1:04:27Speaker 01

  Sure. It's very exciting for me to talk about it. When I came to New Amsterdam with John, John said, Michael, I want to hear your story about Alzheimer's. And I said, let me go through it with you because we had, what we had at the time was a Mendelian 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 function. So they had a CTP and they had less. Then later came the data showing that if you have ApoE4 and you have a CTP loss of function, your risk of Alzheimer's is significantly mitigated. So we had genomics validation.

• 1:05:10Dr. Peter Attia?

  What was the phenotype lipid wise of those patients?

• 1:05:13Speaker 01

  Well, they have high HDL.

• 1:05:15Dr. Peter Attia?

  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.

• 1:05:25Speaker 01

  And they have very low small LDL and they have very high large LDL particles. And it's what CTP inhibition does.

• 1:05:33Dr. Peter Attia?

  And so, Michael, what was the degree of risk reduction in those ApoE4 patients?

• 1:05:38Speaker 01

  Well, look at the curves. It basically took the E4 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.

• 1:05:49Dr. Peter Attia?

  Wow.

• 1:05:50Speaker 01

  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, a McGill, a PhD researcher, had done some really great work on CTP. So 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, they.

• 1:06:28Dr. Peter Attia?

  Wait, I'm a bit confused. You're saying you take a mouse that doesn't have CTEP.

• 1:06:34Speaker 01

  And you give it a CTEP.

• 1:06:35Dr. Peter Attia?

  And you give it a CTEP inhibitor?

• 1:06:37Speaker 01

  Right.

• 1:06:38Dr. Peter Attia?

  Why would that change anything if they don't have it in the first place?

• 1:06:41Speaker 01

  You gave the CTP.

• 1:06:41Dr. Peter Attia?

  Ah, I got it. Okay.

• 1:06:42Speaker 01

  You gave the mouse the CTP gene.

• 1:06:44Dr. Peter Attia?

  Yep, then you block it.

• 1:06:45Speaker 01

  Giving CTP, first of all, made the dementia worse. And then you give the 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. Unfortunately, in the biotech world. Alzheimer's does not, it's a huge graveyard, yeah. And it's really hard to get funding for Alzheimer's studies. But we had another, obviously the LDL and the cardiovascular. So we raised $200 million in our series A. We got 1 million allocated for Alzheimer's research at the beginning.

• 1:07:21Dr. Peter Attia?

  When did you go public?

• 1:07:22Speaker 01

  2022. So we started the company in 21, early 21. We started the funding and then we went public in the end of 22. So that was the basis of our genomic data. We had the animal data. We also had a lot of data on HDL being somewhat protective against Alzheimer's. We had a lot of data on that. Mixed data, not entirely convincing, but number of studies showed HDL, high HDL was protective against Alzheimer's, especially APOE1, which is the protein carrier for HDL. That's where we started. And so then with our funding, we were able to do a small study in Amsterdam where we looked at about 13 APOE4 with impaired cognitive function, mild cognitive impairment.

• 1:08:04Speaker 01

  We gave them obacetropib and we saw some improvements in lipid metabolism. APOE4, by the way, is a lipid gene. Let's back up and start about what about APOE4 is detrimental. And that's the key because you're talking about where does obacetropib fit in? We have the LPLA, we have the diabetes benefit, the small particles. But also the fourth leg of that is for APOE4, you also have high LDL as well and lower HDL. So it becomes another good drug to consider. That's 25% of the population. So you can see where obacetropib becomes a really good add on the statin option if you have any of those characteristics.

• 1:08:43Dr. Peter Attia?

  And so let's talk about the homozygous E4 patient. What is happening in their brain as a result of the homozygosity? Because again, it's a very subtle change in their APOE protein due to that gene. And how does it manifest itself in the brain? Cholesterol metabolism?

• 1:09:04Speaker 01

  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. But first of all, the brain is a very cholesterol-rich organ. If you look at, don't hold me to exact numbers, but 2% of the dry weight of the brain is, 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. And it's a big part of what the brain is all about. And cholesterol is synthesized very avidly by the neurons during your childhood growth phase.

• 1:09:47Speaker 01

  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. Now, the complicating thing is the blood-brain barrier completely separates off the brain lipid metabolism from the rest of the body. There's no APOB in the brain. There's no APOB.

• 1:10:29Speaker 01

  It's all APOE and HDL in the brain. There's no connection between LDL and the plasma 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. And 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.

• 1:11:02Dr. Peter Attia?

  I had no, I had never even thought of that, Michael.

• 1:11:05Speaker 01

  Yeah, so that's the connection.

• 1:11:06Dr. Peter Attia?

  Do you think there's any clinical significance to that in organ transplant?

• 1:11:10Speaker 01

  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.

• 1:11:19Dr. Peter Attia?

  We don't think so.

• 1:11:20Speaker 01

  We don't know. We're still, it's still thought.

• 1:11:22Dr. Peter Attia?

  That's super interesting.

• 1:11:23Speaker 01

  Yeah, so APOE4, there's a 2, 3, and 4. Most people are 33s. There's about 20, 25% are 34s. And then about 2%, so 3% are homozygote E4s. So E4s, your homozygote, about 10 times risk of Alzheimer's. The 34 is about 3 times risk. 33s are average. And then if you're 2, which is the best, your risk is lower and you have longevity. It's one of the best longevity genes to be in APOE2. So that's the breakdown. So, so when you have APOE4, what happened? So APOE is made by the astrocytes. It appears that they have impaired cholesterol efflux and lipidation when you have APOE4.

• 1:12:05Speaker 01

  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, another cholesterol. So the blood-brain barrier protects all that. But there is one cholesterol that goes through, it'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, it gets inflammatory. And then amyloid and tau follow. Alois Alzheimer's first described Alzheimer's, it was amyloid plaques, tau tangles, and basically lipid deposits.

• 1:12:50Speaker 01

  And so when you have APOE4, you can't clear the lipid as well. And that sets up the whole Alzheimer's cascade. And then they get Alzheimer's roughly, one 4 gives you Alzheimer about 10 years earlier. So 24 is 20 years earlier, that kind of thing. So it's a very well-established risk having the APOE4 genotype. So that's the background about APOE4 and it's a lipid gene. And what is important about obacetropib is that we had that genomic data, we had the animal data. And then we know that HDL is the one lipoprotein that does interface with the brain. We don't think APOE1 is actually made in the brain. It comes from the periphery. APOE1 would be the protein carrier.

• 1:13:34Dr. Peter Attia?

  Yeah, I thought it was made in the liver. You're saying if the brain's APOA1 is made in the brain or made in the liver?

• 1:13:39Speaker 01

  Most of it, we believe, comes from HDL from the plasma, not.

• 1:13:44Dr. Peter Attia?

  Not from the brain, yep.

• 1:13:45Speaker 01

  It may be made in the brain, but we don't think so. We think it's made, it comes across the blood-brain barrier. And so we know that for sure in the coronal plexus, which is the blood-brain barrier interface.

• 1:13:57Dr. Peter Attia?

  And this is just mechanical? It's because HDLs are so much smaller than LDLs?

• 1:14:00Speaker 01

  Right, with small HDLs. But SRB1, which is the receptor for, we talked about that, is heavily in the blood-brain barrier in the coronal plexus. So the only thing that really interfaces with the brain from outside the brain is HDL. And so having high HDL can help remove the excess cholesterol that APOE4s can't metabolize effectively. And also, we proved this, it delivers antioxidants to the brain. Very important to reduce the inflammatory response. We know that, and also maybe DHA even can be delivered by HDL. But certainly it's acting like it does. It's the removal system, amyloid even, amyloid can be removed by HDL. So we believe that the HDL going up and interfacing with the brain can help mitigate

• 1:14:44Speaker 01

  the APOE4-related Alzheimer's risk.

• 1:14:47Dr. Peter Attia?

  What about in the non-4s?

• 1:14:49Speaker 01

  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 you, again, you stop making cholesterol in the neurons, your neurons are dependent on, on astrocyte cholesterol function and so forth. And as you get older, you know, these things tend to get less effective. So we think that that part could also be mitigated by, by raising HDL through obacetropib's mechanism of action.

• 1:15:19Dr. Peter Attia?

  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 the opposite, just on an individual basis, is there some risk that statins would be driving Alzheimer's disease?

• 1:15:43Speaker 01

  I mean, just the opposite, actually. I mean.

• 1:15:45Dr. Peter Attia?

  Yeah, I guess my question, sorry, should be, why do we not see that? Why do we see the opposite in the clinical trials?

• 1:15:51Speaker 01

  About not protecting against Alzheimer's?

• 1:15:52Dr. Peter Attia?

  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.

• 1:16:00Speaker 01

  Yeah. We're not sure, I mean, the big statin trial that looked at Alzheimer's didn't show a benefit, it did not work. That's not necessarily the means that statins can't protect against Alzheimer's, which I think they potentially can. But in the study that was done, actually done, it didn't work.

• 1:16:14Dr. Peter Attia?

  Yeah, it was a wash.

• 1:16:14Speaker 01

  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.

• 1:16:23Dr. Peter Attia?

  Yeah, I think that's fraught with issues. I prefer these secondary analyses on randomized control trials.

• 1:16:28Speaker 01

  Yeah, yes. Listen for that, when people ask about this all the time and you can say, at least, based on observational data, there's no increased risk of Alzheimer's. First of all, I just want to get them over the hump, that's not going to increase the risk of dementia, because you hear that, we really focus on that. Protection issue. It's a hard sell to say it actually prevents against Alzheimer's because we don't think it gets to the core reason. It can't affect lipid metabolism in the brain the way obacentropib potentially can.

• 1:16:53Dr. Peter Attia?

  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. And so you're seeing this reduction in vascular dementia, but it's just being counted as overall dementia, but not pathology specific.

• 1:17:24Speaker 01

  That's absolutely true. I mean LDL is a dementia risk factor.

• 1:17:27Dr. Peter Attia?

  But it might not be an Alzheimer's risk factor through this mechanism.

• 1:17:30Speaker 01

  It's a stroke benefit. So we think that obviously the obacentropib having LDL lowering can benefit stroke, but also we do believe or hope that we can show an Alzheimer's prevention benefit. Talk about what we showed already, but we're playing another study to look at it more carefully this year to look at the benefit of obacentropib on prevention of Alzheimer's.

• 1:17:51Dr. Peter Attia?

  So let's talk a little bit about what you saw in your biomarkers to kind of validate all of these hypotheses.

• 1:17:57Speaker 01

  The first study that was a pilot study showed that we did, in fact, reduce 24 hydroxy and 24.7, the sterols in the CSF went down. You've not seen that with statin, so it was a difference.

• 1:18:10Dr. Peter Attia?

  And so how did you, did you?

• 1:18:11Speaker 01

  By CSF. Right. We see measured CSF in these patients. And we saw that the 24 and 27 hydroxy went down. We saw stabilization of biomarkers. And we saw cognition stable. We also saw had a few anecdotal cases of patients really having quite a beneficial effect on cognition. It was a pilot study with not power, open label. But we saw target engagement with 24 and 27 hydroxy going down. We also, in another analysis, showed antioxidants in the CSF going up. We had target engagement that we are, in fact, removing these potentially toxic sterols and improving antioxidant levels in the CSF. So that's a proof of concept study that we did.

• 1:18:55Dr. Peter Attia?

  Tell me about those patients. Did you say those had MCI?

• 1:18:57Speaker 01

  MCI. All had MCI, yeah.

• 1:18:58Dr. Peter Attia?

  And just explain to folks clinically how patients with MCI would be behaving.

• 1:19:03Speaker 01

  They do a cognitive testing. There's all different types of scoring systems, but when you do the memory testing and functional testing, they score showing they have impairment. But what's important about Alzheimer's and why we're focusing on it is that we're learning now, the abnormality starts 20 years before there's even MCI. There's a long lag period between when we start seeing the pathology, the amyloid and the tau and all the biomarkers going up, and actual MCI. And MCI, of course, then has different levels until you get to the functional impairment where you're now, this is actually subjective cognitive impairment where people think they have impairment. When they do the testing, they're still pretty okay. And then you have those that are truly cognitively impaired. Yes.

• 1:19:49Dr. Peter Attia?

  So just so folks understand what we're talking about here, which is Alzheimer's is not a disease of old age. It's a disease of middle age that presents in old age. And that's saying exactly what you just said in a different way. I mean, that's in some ways a frightening thing to think about, but it's just the reality of the disease. And it also speaks to the lens through which we want to consider prevention. I would argue the same is true of cardiovascular disease. It's a disease of middle age. It presents in old age for most people. Unfortunately, for someone like your father, it presented in middle age, but it starts effectively the moment you've got these LDL particles circulating. And so what would you say is the canary in the coal mine that is measurable? Would you say that it is the presence of PTau?

• 1:20:29Speaker 01

  Yep. That's what's exciting about the field right now. Like I said, I came from the LDL world. Your LDL became a great causal, well, I was invited, 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. Yeah. 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 have neurodegeneration. And so I think we're way too late in how we treat Alzheimer's. So if we can find a prevention therapy.

• 1:21:08Dr. Peter Attia?

  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 head cardiologists had the misfortune of trying to use lipid lowering therapy to treat heart failure. We may never have developed lipid lowering drugs.

• 1:21:43Speaker 01

  That's right. They would start with heart failure, it would all been failures. We did heart failure trials and didn't work. So with statins.

• 1:21:48Dr. Peter Attia?

  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. So it's a very unfortunate consequence of the pathology, though an understandable mistake on the part of pharma because that's the hand you're dealt. You have to do clinical trials.

• 1:22:18Speaker 01

  Right, right, right. I hope that PTau 217, which is what we found in our, can ultimately become a biomarker for regulatory approvals. Just we're not there yet.

• 1:22:28Dr. Peter Attia?

  How does it differ from PTau 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 PTau versus AB4240 and some of the other biomarkers that are becoming more common now?

• 1:22:45Speaker 01

  Sure, sure. Yes, a little bit of a background on these biomarkers. So they're all, when we did our first pilot study, PTau 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 new biomarker called PTau 217. If you can show over a year with our existing study with in Broadway, that you're reducing PTau, that would be a great validation that what you saw in your pilot study is truly an effect. That's what we did. So PTau 181 and 217 are both tau measurements, but they correlate with amyloid in the brain. They're very strong predictors of amyloid

• 1:23:27Speaker 01

  on PET. And so if you look at centoloids of amyloid, which is the gookey stuff in the brain, the protein aggregates and so forth, the misfoldings, the amyloid tau 217 and 181 predict that very well. In fact, in some ways, I think the PET could be archaic relatively soon based on these biomarkers.

• 1:23:48Dr. Peter Attia?

  That's a big deal, given the radiation and the cost associated with those tests.

• 1:23:52Speaker 01

  From what I look at the literature, I mean, they're as good as the PET almost on area of the curve. So they're very good at predicting amyloid on the PET. They're very good at predicting progression of disease from normal to MCI. They're very good looking at MCI to full blown stage two or three Alzheimer's. And even progression of Alzheimer's is also predicted by PTau 217. So PTau 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 PTau, which is maybe even better, but still, that's still early. So that's a tau. It's amyloid first, and then tau. And there's this conversion of amyloid

• 1:24:34Speaker 01

  to tauopathy, which is a critical transition in the disease process where the amyloid is that gookey stuff, and then tau itself is the one that really drives the neurodegeneration that occurs later. So it's first amyloid, then a lot of tau, and then you're basically, unfortunately, it's too late.

• 1:24:56Dr. Peter Attia?

  PTau 217 is not a CLIA approved assay, is it?

• 1:25:00Speaker 01

  Well, this 217, yes, it is CLIA, and it's divided by amyloid 40, A beta 40, that got approved this past year.

• 1:25:09Dr. Peter Attia?

  Sorry, you mean the ratio of?

• 1:25:11Speaker 01

  PTau to amyloid is approved.

• 1:25:14Dr. Peter Attia?

  It is approved?

• 1:25:15Speaker 01

  Yeah.

• 1:25:15Dr. Peter Attia?

  Okay. So AB4240 is CLIA approved by itself?

• 1:25:19Speaker 01

  Right.

• 1:25:20Dr. Peter Attia?

  PTau 181 is CLIA approved by itself?

• 1:25:22Speaker 01

  Yeah. If it's not approved already, it'll soon be approved. It's being used a lot.

• 1:25:26Dr. Peter Attia?

  217 not by itself, but in ratio is an approved?

• 1:25:30Speaker 01

  Right, right.

• 1:25:31Dr. Peter Attia?

  Okay. And do you think that the ratio of PTau 217 to AB4240 offers a benefit over PTau by itself?

• 1:25:39Speaker 01

  Well, the data's actually kind of mixed. There's actually PTau 217 alone looks awfully good. Whether the ratio is better, I've not.

• 1:25:47Dr. Peter Attia?

  So you guys did your own assay for that?

• 1:25:49Speaker 01

  We do standard assay for 217. It's called, it's quantaric, which is one of the standard ones. There was something called precivity, which does the PTau 217 with A beta 4240. But we look at all the biomarkers. We looked at PTau 217, PTau 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. And then we had the ratio, 4240 ratio, then neurofilament light, which is a later-stage inflammatory biomarker. I mean, you see a lot in injuries,

• 1:26:31Speaker 01

  but as well as multiple sclerosis or ALS, those kind of things. Disease in Alzheimer's too, but later in Alzheimer's. We had our whole study, Broadway, 2,500 patients, and we had a sample that we could do, it was prespecified analysis. We did analysis at the beginning and then 12 months at the end of all these biomarkers, with PTAL217 being our critical one to look at. We found that overall, there was a reduction in PTAL217 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, 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

• 1:27:14Speaker 01

  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 risk. And so what we found was, overall, it worked. The people that were older, it worked even better. If you worked at people that had E4, it worked even better. And if they were 44 homozygotes, we saw this profound benefit on not just PTAL217, over 20% difference from placebo, but all the biomarkers improved. 181, amyloid 4240, GFAP, neurofilament light, all got better with obacetropib. And that's what we published in our paper. So, we felt

• 1:27:59Speaker 01

  that this data really confirmed that obacetropib was in fact, active in potentially preventing Alzheimer's disease.

• 1:28:08Dr. Peter Attia?

  Now, how do we know how to interpret whether those will end up being, maybe the answer is we don't, but do we have a sense of if this could translate to a clinically meaningful benefit, to a reversal of disease, a halting of disease, something of that effect? Or is it your belief that that could probably only happen if we establish causality through trials like this, and then take the same playbook that we took with cardiovascular disease, which is move up 20 years, start treating before any of these things are even remotely present, and just hope that that alone prevents even the development of the pathology?

• 1:28:42Speaker 01

  Yeah. The answer is, I don't know. The field is evolving, and the regulators have to help out here, because right now, PTAL217 cannot be an endpoint for regulatory approval. It does require improvement in cognition, which might be an impossible thing to show.

• 1:28:58Dr. Peter Attia?

  Unless you took for decades.

• 1:28:59Speaker 01

  What we can say is that for us, we're going to go ahead with another study. We do know that the ApoE4 community, there's a new alliance of patients out there that are advocating for treatment. It's like any genetic disorder, they don't want to wait 10 years, they want something now for treatment.

• 1:29:17Dr. Peter Attia?

  Don't you think it'll just be used off-label for that reason, anyway?

• 1:29:20Speaker 01

  Well, we can unfortunately...

• 1:29:22Dr. Peter Attia?

  You have nothing to do with that, but I'm just saying, like, look, people were using PCSK9 inhibitors off-label for LP little a reduction, the moment it became clear that it was lowering LP little a 20 to 30%. Now, we have no idea if lowering it 20, 30% mattered, but it seems that it's not unheard of for people to take off-target use. There are plenty of people using GLP-1 agonists today for neuroprotection, even though that would still be considered sort of off-label as well.

• 1:29:45Speaker 01

  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 PTAL217, with enough advocacy, can become a regulatory endpoint. For this reason, I mean, it's so good.

• 1:30:01Dr. Peter Attia?

  Let's take the flip side of that. The Feynman argument, that in science, the easiest person to fool is yourself, or the goal of science is not to fool yourself, and you're the easiest person to fool. So what would be the flip side argument? What would be the case for 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?

• 1:30:24Speaker 01

  You're proving a biomarker, but you're not treating the underlying disease. But it is the disease. I mean, that's the actual tau that's in the brain that leaks out into the plasma. So it is a, if we're using these anti-amyloid antibodies, or now they're working on anti-tilly antibodies, and there's still got a ways to go. Obviously, those anti-amyloid antibodies have some very modest benefit, but not for ApoE4 homozygotes. So I do feel that the homozygotes in particular, which are the ones that we know 100% go on to get Alzheimer's if they live long enough. Like a lot of other rare diseases allow these surrogates to get approval based on a surrogate that which may or may not translate to a clinical benefit.

• 1:31:02Dr. Peter Attia?

  Yeah, I'm thinking less of it from a regulatory question, and more just from a biologic question of, it's easy to get fooled. We can all be fooled. I mean, HDL fooled everybody for decades. For decades, people were chasing the wrong thing, and they had all the epidemiology to back it up. But at the end of the day, it didn't matter. I'm not saying this is the case, I'm not even suggesting that it looks likely that that's the case, 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 PTAL thing that took us down a rabbit hole, what a waste of time and money that was, we didn't save a single life. I wonder what the story would be? What would be the revisionist explanation of that?

• 1:31:47Speaker 01

  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 PTAL217. On the other hand, the trailblazer anti-amyloid trials, Lily showed a pretty high correlation between improvement in cognition and PTAL217 going down. We're getting more data, and we're going to do our own study. We are going to do a study with 300 patients that have pre-Alzheimer's, you want to call it. They have evidence of higher tau levels based on their ApoE.

• 1:32:22Dr. Peter Attia?

  With MCI?

• 1:32:23Speaker 01

  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.

• 1:32:29Dr. Peter Attia?

  MCI is like early heart failure.

• 1:32:31Speaker 01

  Right, right. We know the brain is already shrunk and all that stuff. Inflammation has set in, the cascades, the tauopathy 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 prespecified analysis. 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 wasn't only 30 patients that had homozygote E4, just the kind, but it was 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.

• 1:33:16Dr. Peter Attia?

  I am surprised to hear that, Michael, given the number of bullet holes that have been fired through so much of that, right? I mean, including some of the fraudulent work that was done in the last decade on this front. Why do you think that they're still clinging so hard to that story?

• 1:33:33Speaker 01

  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.

• 1:33:49Dr. Peter Attia?

  Because of ARIA, or it just doesn't?

• 1:33:51Speaker 01

  Oh, ARIA, ARIA is what I'm talking about. It doesn't work as well on the cognition improvement. I mean, that's...

• 1:33:55Dr. Peter Attia?

  And you have the higher risk of...

• 1:33:56Speaker 01

  ARIA, so they don't give it, there's supposed to be a contraindication to use it in E4 homozygotes.

• 1:34:00Dr. Peter Attia?

  That could be the same question. Is it that anti-amyloid drugs could be beneficial, but they have to be started 20 years sooner?

• 1:34:07Speaker 01

  And then 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?

• 1:34:17Dr. Peter Attia?

  Especially if the side effects are potentially catastrophic.

• 1:34:20Speaker 01

  Yeah, right, right. So that's going to be a tough sell. So we're trying to find over 60, we're trying to pick like, maybe age 60. Could we know from our Broadway data, who are the rapid, more rapid progressors? Who does tau go up the most in? And it is obviously E4 is the older, even the diabetes, that makes the amyloid. So I think that we'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 the results of the next trial.

• 1:34:51Dr. Peter Attia?

  Well, this is incredibly exciting. So again, the hope here would be that we see approval in the United States, following the European approval by a period of a year or two for cardiovascular disease. And in parallel, we see the right clinical trials being done on AD prevention. And this would make it a first. There would be no approved drug out there for AD prevention. Yeah, there's so much more we could talk about on this. But I do want to spend time on a topic that we talk about from time to time, but I have a feeling you're going to add a lot of value to my somewhat limited knowledge, which is the most up-to-date thinking on the role of fish oils, DHA and EPA. But you want to talk about it through cardiovascular disease first, or talk about it through?

• 1:35:36Speaker 01

  Alzheimer's.

• 1:35:37Dr. Peter Attia?

  Alzheimer's, or both?

• 1:35:37Speaker 01

  I think the cardiovascular part, I'll give a quick answer to that, because I was involved in developing a omega-3 for heart disease called Epinova. We went to an outcome study, and it didn't work. But it was DHA and EPA, but mostly EPA, had some DHA.

• 1:35:53Dr. Peter Attia?

  And that was four grams? How much?

• 1:35:56Speaker 01

  That was four grams, yeah. It was called the strength trial. I think what I learned, in fact, because I'm always 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 anti-thrombotic effects. EPA is antagonizes the arachidonic acid pathway, and has like a anti-thrombotic effect, anti-inflammatory effect. And so there was really two reasons to think why omega-3s could lower risk. And one was through the EPA anti-thrombotic 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, but it was 50/50 primary. And so if I had to do it all over again, I would have made it all secondary, just like mostly the REDUCE-IT

• 1:36:41Speaker 01

  trial was, which is the EPA-only trial. So the REDUCE-IT trial showed a benefit, and it could have been, likely had some effects of the mineral oil placebo, tilting it a little bit.

• 1:36:53Dr. Peter Attia?

  I've heard this explanation before, but say a little bit more about why mineral oil as a placebo could have been harmful.

• 1:36:58Speaker 01

  But you'd actually look at the inflammatory signaling and increased inflammation. And so it had some inflammatory, Paul Ridker helped now analyze that from the REDUCE-IT study. It also may affected absorption of statins, because LDL levels went up. LDL's level went up about 10%, so 9 to 10%. I think it showed that EPA works, APO works. It may not have been the 25%. That people think it was, but it still worked. You take all that away, it still worked. EPA only worked. And then the strength trial didn't work overall. It may have worked on secondary branch in a, not post hoc, but in that population.

• 1:37:35Dr. Peter Attia?

  And the placebo and strength was what?

• 1:37:37Speaker 01

  It was corn oil.

• 1:37:38Dr. Peter Attia?

  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 you're doing apples to apples.

• 1:38:01Speaker 01

  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, it shows a benefit for pure EPA. Then we then had the prominent study, which is the triglyceride lowering trial with a fibrate. Pima fibrate showed no benefit. It's very similar to the strength trial population. What that says is that EPA does work on reducing events.

• 1:38:31Dr. Peter Attia?

  But not through triglyceride lowering?

• 1:38:32Speaker 01

  Not for triglyceride lowering. It's more for the anti-thrombotic, anti-inflammatory effect. Which brings me to DHA. So DHA, I still think has a lot of health values that we should talk about, especially for the brain. Because the brain is predominantly DHA. That's the fatty acid in the brain. Now, the problem is with DHA, we tried DHA supplementations on cognition, didn't really show much. You've had the same Yaseen 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. They have a true DHA deficiency in the brain to some degree. A new discovery, which is very exciting, is the MFSDA2 transporter, MFSDA2 transporter.

• 1:39:13Speaker 01

  It's a transporter across the blood-brain barrier for DHA. It turns out that DHA prefers the lysopC form, the lysophosphatylcholine 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. And 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.

• 1:39:45Dr. Peter Attia?

  Completely independent of the clot work?

• 1:39:47Speaker 01

  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. I mean, I think it can make some, but you have to get DHA from the periphery.

• 1:40:13Dr. Peter Attia?

  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%.

• 1:40:33Speaker 01

  Right.

• 1:40:33Dr. Peter Attia?

  Your belief is they are probably lowering cardiovascular disease risk, but probably not having an impact on Alzheimer's disease risk, given the inability to get the DHA in the brain?

• 1:40:43Speaker 01

  You have to get the lysopC form to get to the brain. You have very limited capacity to convert that into the lysopC form.

• 1:40:50Dr. Peter Attia?

  Well, yeah, absent another.

• 1:40:51Speaker 01

  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.

• 1:41:08Dr. Peter Attia?

  But there is no version of that on the market today?

• 1:41:11Speaker 01

  It's coming. It's coming, yeah.

• 1:41:12Dr. Peter Attia?

  But will it be a drug or will it be a supplement?

• 1:41:14Speaker 01

  It'll be a dietary supplement, yeah.

• 1:41:16Dr. Peter Attia?

  Do you know who's making that?

• 1:41:17Speaker 01

  One is already available krill oil base, but there's one with fish oil base coming. In Jocasta, we're going to do the science behind that as well.

• 1:41:24Dr. Peter Attia?

  For a drug or for a supplement?

• 1:41:26Speaker 01

  For a supplement, yeah.

• 1:41:27Dr. Peter Attia?

  Okay. You've been involved in so many clinical trials over the course of your life, and there's so much discussion about AI in medicine and the impacts it can have. But I'd have a hard time thinking of a more important impact that AI could have on medicine 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 course of human history. Where do you see AI factoring into what appears to be the long pole in the tent, which is doing clinical trials?

• 1:42:10Speaker 01

  It's a hard thing. Until there's regulatory reform, I hate to say it. I mean, I know that's a tough thing to advocate for because first of all, you have to figure, how do you do the data? It's still, like, everyone's tried to say, can we make clinical trials a lot more streamlined? Less data collection. But also, to me, I wrote a paper about this. Why can't we look at clinical trials based on using AI? Who, if you took the drug the right way, how well did it work? Instead of, we have to get diluted by everyone who stopped the drug, who wasn't compliant.

• 1:42:44Dr. Peter Attia?

  Yeah, so in other words, make the efficacy not based on intention to treat, but on actual compliance.

• 1:42:50Speaker 01

  Right. And that would be a huge difference already. Your effects are diluted so much by, especially for long studies, you have to drop in. So you can use AI modeling even to show that for those who took the drug, took it the right way, the benefit was, worked well.

• 1:43:07Dr. Peter Attia?

  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?

• 1:43:17Speaker 01

  We actually, there's what's called on-treatment analysis or kind of looking at PK, you know, who was the right, taking the right drug. It always works so much better.

• 1:43:24Dr. Peter Attia?

  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?

• 1:43:36Speaker 01

  You want to see 80%. That's kind of the benchmark, yeah. In fact, when you do your protocol analysis, you say anyone below 80% compliant.

• 1:43:45Dr. Peter Attia?

  But the FDA will never accept per-protocol analysis?

• 1:43:47Speaker 01

  No, no. But they should. I mean, that's the thing. When I put 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 harder to do these studies.

• 1:44:11Dr. Peter Attia?

  Because of the ubiquity of drugs on the market already? And then the amount of LDL lowering that's already in the baseline?

• 1:44:17Speaker 01

  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.

• 1:44:29Dr. Peter Attia?

  So let's come back to statins for a moment. What do you think is the best explanation for the increase in the incidence of type 2 diabetes that we see in statins? Again, it's not small, but it's a real signal. I'm sorry, it's not large, it is small. It's a real and undeniable signal. And by the way, I would say that it's not just patients going on to get type 2 diabetes, it's insulin resistance. Patients who don't progress all the way to type 2 diabetes, we do see an increase in insulin resistance. What do you think's explaining that?

• 1:44:51Speaker 01

  Well, first of all, it looks like all LDL lowering drugs, even PSK9s, have a little bit of a diabetes signal, except for obacetripim. I mean, just the opposite.

• 1:45:01Dr. Peter Attia?

  Versus the opposite?

• 1:45:02Speaker 01

  Yeah. It is about LDL.

• 1:45:03Dr. Peter Attia?

  But that's not entirely true. Don't bile acid sequesterants, which lower LDL, albeit somewhat weekly, show an improvement in glycemic control?

• 1:45:11Speaker 01

  Right. I published a paper on that, too. I mean, so, but I'm talking about the mandilium minimization work. We look at diabetes and LDL, you see a consistent, except for the bile acid sequesterant part, I'm not sure what the drug matching for a gene would be, but it's not that often. The bile acid sequesterant gene matching is not an easy one. But you're right. But bile acids are very energetic. They take a lot of steps to make a bile acid. So you look at, when you have a bile acid removal, you got to make a new one. So that creates energy requirements. So you can see how blocking a bile acid from being reabsorbed, which is why you reabsorb it, so you don't have to worry about making it again,

• 1:45:50Speaker 01

  can ultimately reduce potentially blood sugar because it is lining up energy that you need to replace. That's my simple thinking about bile acids.

• 1:45:59Dr. Peter Attia?

  Are there any patients that are in your clinic that are still on a bile acid sequesterant?

• 1:46:03Speaker 01

  Yes, there are some, yes.

• 1:46:04Dr. Peter Attia?

  These are patients that can't tolerate any other drug or can't afford?

• 1:46:08Speaker 01

  Or they have hemochystolemia, and they need, we have some, yeah.

• 1:46:10Dr. Peter Attia?

  And how much LDL lowering do you get?

• 1:46:12Speaker 01

  About 10 to 15%. It's not great.

• 1:46:14Dr. Peter Attia?

  And the side effects?

• 1:46:15Speaker 01

  The GI side effects. There's some that are better. We see them a lot. We don't use them that much anymore with, once azetimibe came into play, because it's pretty much the same as azetimibe, but azetimibe's a lot easier to take.

• 1:46:25Dr. Peter Attia?

  And does azetimibe have an increase in insulin resistance associated with it?

• 1:46:29Speaker 01

  The data suggests clinically not, but I think genomically, there is a slight signal there. The MPC101, the knockout types. But certainly, PSK9 inhibitors genetically have that.

• 1:46:40Dr. Peter Attia?

  So what do you think is the mechanism for that?

• 1:46:42Speaker 01

  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 been other things, too. I mean, the beta cell preservation and so forth. I don't know. It's been an enigma about why. I don't think anyone knows for sure. But we do know a couple of things that I think are helpful. One, it is dose-related. It is age-related. It's weight-related. So if you have those high dose, older, obese, you know, more common. To get to our point earlier about not being on high-intensity statins, why is it worth the six, whatever it is, four to six percent? Why not go at a lower dose and lower risk? It's more about how do you mitigate the risk? No, the MA,

• 1:47:25Speaker 01

  it is a, 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.

• 1:47:34Dr. Peter Attia?

  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, understand it, move to combination therapy to lower statin dosing, I think it becomes less and less of an issue.

• 1:48:07Speaker 01

  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 statin.

• 1:48:22Dr. Peter Attia?

  How many other CTEP inhibitors are in the pipeline at the moment?

• 1:48:25Speaker 01

  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 obacetropib. It's got a low dose, extremely well tolerated in our clinical trials.

• 1:48:37Dr. Peter Attia?

  Remind me, the molecule that, when you guys bought it, came from?

• 1:48:40Speaker 01

  Well, Amgen through Mitsubishi, Japanese company, first discovered it. It was sold to Amgen and we got-

• 1:48:47Dr. Peter Attia?

  What were they doing? What was Mitsubishi doing when they were discovering it? Were they doing it specifically for the purpose of following the earlier CTEP inhibitors? And then they sort of abandoned it?

• 1:48:55Speaker 01

  Well, they wanted to make a better CTP inhibitor. So one that had no fat uptake, much lower dose, more potency, more bioavailable. And so they gave us, we got a great drug. We got a great drug to work with. It's going to be very hard to match the profile that obacetropib has from a pharmacokinetic perspective.

• 1:49:12Dr. Peter Attia?

  And to give folks, again, just a sense of what does it take to develop a drug? So if you look at the money you paid to acquire the drug, what you had to raise through the clinical trials, and what it would take to get to approval, what's the approximate dollar amount to do that?

• 1:49:26Speaker 01

  It's well over a billion. But this, not accounting what it was cost up until we got it. I mean-

• 1:49:30Dr. Peter Attia?

  Yeah, it's a billion of new Amsterdam plus all the money that came before it to get it into Phase II. Yeah. So the average drug right now is about $3 to $4 billion to approval.

• 1:49:41Speaker 01

  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.

• 1:49:58Dr. Peter Attia?

  What do you think overall of the landscape of biotech investing? I mean, we live in this world now where AI is clearly the most interesting and exciting thing to invest in. Capital is flying into AI. It doesn't really matter that lots of people are saying, hey, look, this is a bubble. We need to be a little more cautious with how we do this. This feels like 1999 for the internet, et cetera, et cetera. But it's so interesting when you look at biotech companies that, I mean, it's very, very difficult to raise money. Where do you think we are in the biotech life cycle? And do you think biotech is just forever going to be complicated because of the time horizon?

• 1:50:35Speaker 01

  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 lists are coming, all of them. In order to grow, they have to get new product. I think in the way the system's set up, you know, everything ultimately goes generic. And so if you see where that is, if companies even want to grow three or four percent per year, which is pretty miniscule growth, they gotta add a lot of new products to their pipeline. The way it's worked out is the big companies also have become pretty dysfunctional on innovation

• 1:51:15Speaker 01

  about developing new drugs. The small companies can be a lot more nimble, a lot more flexible, take more risk and don't have to worry about corporate kind of hierarchy to make a decision. We feel that biotech is right now in a really good position, and I think AI is going to help a lot. I hope we can figure out a way to make clinical trials a lot more cost-effective and lower cost, but even drug discovery. China, for example, is just become a huge investment in, for every chemist in the United States, just like 10,000 in China. They have the capabilities to really surpass anything that we can do from a drug development perspective, just by the person power that they have. But that sets up an opportunity. I mean, I

• 1:51:58Speaker 01

  still think we have the science and the innovation, and we have the creativity that could lead the world in coming up with the new ideas. But China is going to be able to have us, be able to take it to the next level, how to 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, Wu Shi, and they figured out a process. And now it's a very robust process and it's going very well. So we hope to be in human clinical trials pretty soon. If you look at it from a global perspective, if everyone could work well together, we have the makings of a biotech revolution, but we continue to have a high benefit to

• 1:52:42Speaker 01

  risk ratio too. I mean, so we have to see how that plays out.

• 1:52:46Dr. Peter Attia?

  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 obacetropib when we spoke about it the first time with John, and everything you've updated us on today only makes that, look, we just can't wait to get this drug into the hands of people, and hopefully not just for cardiovascular disease, but perhaps even more excitingly for Alzheimer's disease, especially in those E4 patients. Anything else you want to talk about on the Clotho front? I know we didn't spend too much time on it. You and I are both involved, which is why I'm a little bit coy to talk about it. I don't want to, I don't like to talk about things that I'm directly involved in as well.

• 1:53:27Speaker 01

  Right. It's moving along well. Like I said, the Chinese, the Wu Shi made a great protein. What we decided, just to kind of step back, where we were a couple of years ago, we had this genomic validation that if you have the Clotho gene, you're protected against Alzheimer's E4 in particular. We had this great animal data consistently showing that if you inject Clotho peripherally, you improve cognition. It went to a primate study and showed great data. And the primates got published in Nature, 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.

• 1:54:04Dr. Peter Attia?

  And by the way, that's a painful point, right? I mean, there's only about, only about 3% of FDA-approved drugs do not have a clear mechanism of action.

• 1:54:12Speaker 01

  Yeah, Metformin does, and is it?

• 1:54:14Dr. Peter Attia?

  Right. Tylenol.

• 1:54:15Speaker 01

  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, we have to kind 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 there is a new fragment that may be cleared that does cross the blood-brain barrier

• 1:55:00Speaker 01

  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, we hope to have human data in roughly a year from now. So we can come back and talk about that with, maybe Dina, together, we can talk about benefits of Clotho.

• 1:55:21Dr. Peter Attia?

  Yeah, it is. It's very high risk, but I know so many of, obviously, the investors in Jocasta, and many of them really come at this through the lens of this is partially a financial investment, but many of them also think of it as philanthropy without the tax break, which is, I'm not just putting my money into this company because I want to make money. That would be great, but what would be greater is if this drug actually works. And I feel like a lot of people take that approach in biotech, especially when it comes to a disease like Alzheimer's disease, where we're just watching people suffer so much right now, with nothing to offer them.

• 1:55:54Speaker 01

  We have to keep working at it. I just lost a double first cousin. My mother's brother married my father's sister. So we have all the same grandparents. She just died at age 72 of Alzheimer's. He was an E4. I've seen it, and I've seen, of course, a lot of patients struggle with it. And I wish we had better advice about what to do. But we do know, I do think maybe we should end with is, what do you do? What if you're an April E4? Like, there are some that say, don't even bother checking it because what can you do about it? I think that's a 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, it's still, and then keeping your, obviously, no diabetes.

• 1:56:32Dr. Peter Attia?

  Normal blood pressure, not smoking, managing lipids. Yeah, there's a lot you can do. I agree with you. I find it very frustrating when people suggest, and by the way, I totally respect a person who says, I don't want to know. Totally fine. Would never force that on anybody. But to suggest that knowing that couldn't provide the motivation to do the things that are hard to do when you're 30 and 40 years old, long before this disease takes hold, I think that's probably the wrong side of that bet for me. But at the same time, 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 weren't important enough. I think when you're looking so hard for things, you start to make signal out of noise. And I

• 1:57:15Dr. Peter Attia?

  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 obacetropib, and then, of course, if they're successful, what that's going to do is open up the door for more things. But what I love about the two of them is potentially they're working by a different mechanism. So I love when you can go after complicated diseases from multiple vantage points.

• 1:57:47Speaker 01

  And it's clear we're going to need multiple therapies. That's the thing. Obacetropib alone could be a preventive strategy. You're going to need more. You need something else as well to make a difference.

• 1:57:57Dr. Peter Attia?

  Well, Michael, thank you for the amazing work you're doing, and thanks for taking the time to come out here today. It was so much fun talking to you.

• 1:58:02Speaker 01

  Yeah, so much fun, Peter. Thank you.

• 1:58:03Dr. Peter Attia?

  Thank you for listening to this week's episode of The Drive. Head over to peterattiamd.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter Atia MD. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute

• 1:58:48Dr. Peter Attia?

  for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up-to-date and active list of all disclosures.