407 ‒ Preventing cardiovascular and Alzheimer’s disease: lowering LDL early, APOE4, and more

Key Takeaway

Treat LDL exposure as a lifetime prevention problem, not a 10-year-risk problem. This week, pull your most recent lipid panel, document your LDL-C, non-HDL-C, ApoB and Lp(a) if available, and review them with a clinician—especially if you have a family history of early heart disease. The actionable goal is to identify elevated risk early and create a durable plan using lifestyle and, when appropriate, medication rather than waiting for plaque, a heart attack, or a misleadingly low short-term risk score.

Episode Overview

Peter Attia speaks with cardiologist and lipidologist Michael Davidson about why LDL should be lowered earlier in life, the evidence behind cumulative LDL exposure, and the evolving role of CETP inhibition. They discuss obicetrapib’s cardiovascular, metabolic, Lp(a), and potential Alzheimer’s implications, with particular focus on APOE4. The conversation also covers dementia biomarkers, omega-3 research, statin trade-offs, and the need for more efficient clinical trials.

Full Transcript

Transcript of 407 ‒ Preventing cardiovascular and Alzheimer’s disease: lowering LDL early, APOE4, and more from The Peter Attia Drive Podcast. Auto-generated from episode audio; may contain minor errors.

Hey everyone, welcome to the Drive podcast. I'm your host, Peter Aia. Michael, thank you so much for coming out and uh it is hard to believe that this is our first meeting in person given how many years we've worked together electronically and in other ways, right? Yes, Chris, great to be here, Peter. For folks who might not be familiar with your work, although we've certainly referenced it a lot on the podcast and your work speaks for itself, so you certainly don't need us referencing it. Um, maybe tell folks a little bit about yourself starting with what you do clinically.

Right. So, I'm a cardiologist, lipidologist, and uh, I run the lipid clinic at University of Chicago. I'm a professor, so I see patients actually, you know, four full days a month. And, and that's and that's a pretty loaded prevention focused practice. And what's the path to that? Right? Because uh lipidology is not necessarily a subsp specialty within cardiology, although of course people who listen to this podcast are very familiar with it and Tom Daypring has been on a number of times. But what was your path towards that from your training?

Were you always interested in prevention? Well, it's a passion because um my father died at age 47 of a of a heart attack. I was 16. Um I had abnormal lipids uh ran into my family. So I uh got very interested in lipids in medical school. So I did the original NASIN trials that went back into the 80s late 70s actually. And then after uh uh training residency I started doing research in my fellowship on omega-3 fatty acids lipids for the lipid effects. So 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. And so that's it's been my passion is to be you know involved in clinical trials and that's how I got so I got into the card I still a cardiologist did the usual stuff that cardiologists do uh but then and then focus primarily on on prevention so I opened a prevention center right out of out of my fellowship along with the re research company that did all the clinical trials and that's been my path you know ever since and then the biotech startups started happening about um about 15 years ago and we have some overlap in some of those companies, one of which we'll talk about.

Um, 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 and um because there really isn't, at least, as I see it, a uniform consensus around how aggressively one should be trying to prevent ASVD. Um sometimes I feel like uh people look at me as though I have multiple heads when I talk about preventing you know taking steps towards prevention in 30-year-olds for example um because by any sort of calculable metric their 10-year risk is very low and would not necessarily justify the steps we might take.

But you're you're more thoughtful. You're you're more you're more you know astute when it comes to all these things. I I'd like to hear your point of view and how you think about primary prevention and we can differentiate that from secondary later on. Right [gasps] now listen it always is a hard cell to get a 30-year-old to start taking a statin for example and so I explain the primordial prevention concept which is you know basically you want to stop plaque from forming before it's there and it's a lot easier to stop it from forming than it is to reversing it when it already exists.

We have this path in 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 [clears throat] that if you have a low LDL throughout your whole lifetime uh it it prevents heart disease in a much greater degree. you know, you know, for example, I mean, if you lower LDL before you have a heart attack, it's very effective.

If you have a heart attack and you lower LDL, it still has benefit, but once you have heart failure, there's no benefit to lowering LDL. And so, the earlier you start, the better. And um what I like is the um the 8 gram rule, which is that 8 grams of cholesterol in your lifetime lead to heart disease. So, so that is 200 mg per deciliter times 40 years is 8 g or 100 milligrams per deciliter times 80 years is 8 g or 80 milligrams per deciliter times 100 years is 8 g.

So you can think about it in that sense that if you we the data says that if you keep your LDL below 80 throughout your lifetime you don't get heart disease. So I think you said this as well. I mean, we have the knowledge to prevent heart disease now. It's applying it earlier in life that really makes the difference. And that's the that's my pitch to the uh to the 30-year-old. And you know, and and and there's a lot of push back and I and I try to then if necessary provide more information to them uh which is you know, 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, you know, plaque analysis. We can look at, you know, other risk factors like LPLA or CRP, things like that, which give us more, you know, kind of information about who's at higher risk. Of course, family history is is so important. Um, but believe it or not, I would think family history one of the most powerful, you know, kind of motivators, but it's not not always the case. Well, it certainly was in you. Um, 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 cardioabolic diseases.

Uh, 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, so you know, whatever my wife's grandfather also died at 47 in the hands of his 16-year-old son. And and it's even so my brother had bypassed at age 44. So it's like even 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. We 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 uh who's also a family doctor went on and and he become a vegetarian really really strict diet uh and um did not take statins until you know much later than at age 44 has has bypass surgery and you know very significant coronary disease. So I think that that kind of like it's a n of one but it's you know it's pretty good comparison you know two brothers one starts statin early one starts statin later and so that that that actually that that decade you know the 30 to 40 decade and even maybe 20 to 30 such an important time frame when the plaque itself is starting to form you know relatively rapidly and that's when you want to have your most effective treatment there to prevent it and that's where I that's why I become um you know an advocate for earlier in life the better when it comes to to start the now with women we have to be careful about the whole pregnancy issue and stuff like that but and and we also still balance that as well but but it's really coming that that type of information I know people bring up you know relative risk absolute risk you know 10ear risk and we you know I think it's really we we're talking about more about you know preventing heart disease when you're 80 or 90 not you know not 10 years from now yeah I guess the other point that for me was a really wonderful um way to think about it that I would credit to Alan Snderman who wrote a paper I feel like it was about 12 years ago but he he at least for me was the first time somebody repositioned the argument of rather than talk about treating 5year risk 10ear risk 15ear 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 have listened to this podcast have probably heard me use the analogy, but it's why we target smoking sessation so aggressively. It's not that everyone who smokes gets cancer, and it's not that everyone who gets cancer smokes, right? Those those those states are true. Um 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 most, but then we're going to have to cut this out." Why? It comes, 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 Mandelian randomizations, let alone the clinical trials, this would be one of the most um assured parts of biology. Um it does become a little uh frustrating that that it's not more widely understood that you have to treat a causal risk factor regardless of the time horizon. Right? And the analogy goes, it's very good. Smoke is a really good one, but also blood pressure, diabetes. We don't wait for stroke and heart failure to treat hypertension.

We don't wait for blindness and kidney disease to treat diabetes. So, I don't know why LDL gets this like stepchild type of role when it comes to how we manage, but it is it is causal and we know that. And so, it's so why not treat it early as you can in life? And I think that's what that's what we advocate for. We're not always successful, but I think we get the message across and we try to uh like I said, we have the tools now if we just apply them much more effectively.

Why do you think that? I mean, not that we should waste too much time sort of speculating, but I don't have a great answer for it, right? 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. Um, and and you could argue, well, is the is the, you know, anti-LDL uh issue really all about drugs? Is it is it that people view it as sort of a pharma conspiracy or something like that?

I mean what what is your take on why um this one issue around LDL has become so contentious? I think it's it's multiple reasons but one actual reason I think is that people believe that LDL cholesterol can be totally managed with lifestyle and it it just if they ate one less egg or you know one one less piece of meat or something like that their LDL would come miraculously down to normal. And I and I think what we're learning from the genomic studies that we you know we do a lot of genetic testing in the lipid clinic we we find that it's almost always a genetic factor involved.

And so when people realize it is genetics and they can't there's nothing they can do about other they're doing already doing great lifestyle and so forth that becomes I think you know part of the the motivation to get them to to do something about it. But uh but it but it's it's it's people don't like taking drugs that I I I get it. It's not a it is about the statin but we we try to find other other ways to get the LDL down if necessary but I wish there was you know more kind of we [snorts] another problem we have of course is the prevent primary prevention guidelines by the like American heart are not very effective they're 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 we would be advocating a much earlier intervention in life.

We just don't have those guidelines that are there to help kind of get physicians on board as well. It's interesting about the lifestyle point because ironically lifestyle has a far larger impact on managing high blood pressure where you know weight loss and exercise uh 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 dysipidemia.

So, I don't know. I I don't I don't uh I don't have any great insight into it, but it it does um uh it does it does make me sad for people who become ultimate victims of it. I do very I see it. I I see the the clinical ramifications of it and it is sad because it's it's preventable. Yeah. But, uh we'll keep we'll keep uh advocating. I think we're starting to see the trend happen. But 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 obese that might be the last you know kind of mechanism once that once that study prevails the prevail trial and then we have a like our 10th different mechanism of action of LDL lowering in benefit then I think hopefully the um you know all the obstacles will go away and people say let's just start treating LDL as early in life as as feasible. Well, let's let's talk a little bit about obeseib. Um, your colleague John Quasterland was a guest on this podcast gosh, I want to say three maybe four years ago.

Um, certainly one of the more enjoyable discussions I've had because I tend to really enjoy talking about these things. Um, 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 CEP inhibition. So let's assume that you know people we're starting from from scratch and uh let's let's talk about this 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.

Um, so take us back to Oh, well, I don't know when the drug entered clinical trials, but I know when it ended, which would have been about 2006. I think it was eight. Okay. Tricep PIV. Yeah, it could have been 2006. I feel like it was the fall of 06. But anyway, might have you're right. It was definitely Christmas December. Got the call. Yeah, somewhere in that range. Yeah. So, it's all right. So first so this is the f and this was fizer combining this with a tovvisat and then a clinical trial.

Okay. So go back to 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 sequesterance. We probably won't get to a zettoi.

We might mention PCSK9 inhibitors but CPEP inhibitors are totally different. So just explain what they do. Right. So I think it's good to start um about what exactly CTP does. It's called cholesterolester transfer protein. It transfers cholesterol you know from HDL into LDL. So when you block it HDL goes up, LDL goes down. And but it also it's many other reasons. It also improves H 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, uh they have very low LDLs, very high HDLs and they get they don't get athoscerosis unless you uh give them give the rat or the mouse CTP transgenically.

Then they get high LDL, low HDL, and they get athoscerosis. It's like the dog, you know, we, you know, the whole uh don't get aththeroscerosis. They're carnivores. They don't have any CTP. Monkeys have CTP. Rabbits have CTP. Humans have CTP. We have, you know, relatively speaking uh high LDL, low HDL. So, and in fact, one of the most prominent um athoscerotic animal models is to give the the mouse CTP. And that and that's what we use in a lot of our studies to show that you can induce athoscerosis and a different therapy can reduce aththeroscerosis.

So it's a very very much a modulator of the LDLHDL levels in in mammals. Do you have a sense given that everything you just described as a mammal um 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 is there a reason you can you can speculate on? It's conservatory. In other words, you didn't have the chasing the woolly mammoth. You didn't have a lot of cholesterol available to you uh in the in the in the Why wouldn't dogs have the same issue then?

Well, they they you know, they they uh they have plenty of meat. They eat all they eat is meat and all that kind of stuff. They they have plenty of cholesterol. So, we think it was truly just a scarcity issue. Yeah, scarcity. I think animals that had more scarce nutrients would want to hyperconerve, right? I mean almost all let's say vegetarian animals don't have you know 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 the how do you think about how CP uh plays a role in in the lipid homeostasis but it's a conservatory mechanism. If you don't if you can't get a lot of cholesterol available from the diet you can it's this way of conserving cholesterol in the body. So when you when you block CTP, you you you lower LDL, you raise HDL, you actually funnel more cholesterol into the intestines. So you you lose a lot of cholesterol in your body by by blocking CP. So the story was it was all about HDL raising because that's what they pro that was the at the time, this is again this is 20 years ago, HDL [snorts] raising was the holy grail.

We had we had data from the Framingham Heart Study that if your HDL was high, you're protected from heart disease. They use the ratio total cholesterol divided by HDL. That was a real, you know, famous ratio that we looked at. It's still a lot of doctors still look at that, you know, as a as a risk predictor. And so raising HDL, we had a couple studies, you know, the the the Helsiki heart study, the VA hit trial using a fibrate lowered HDL, raised HDL a little bit, and it had a some heart disease benefit.

And so everyone's about raising HDL. So, and where were we in our knowledge of nascin's impact on HDL and uh and events? We we only knew nascin alone in the coronary drug project did lower events. We did we did also knew nascin as one of the drugs that was studied. It had alone that's but that was the pre-statin era had a reduction in cardiovascular events in secondary preventionary prevention. Yes. How significant relative to modest? It was modest. Not not nearly the same as statins. No, but it was obviously nasin has a lot of side effects.

It has it I took nasin as before statins because that's what we had. I got you get flushing and GI side effects and and uh liver issues and stuff like that. But no, we had nascin and we had and also raised HDL cholesterol didn't quite a bit like 20 30 that was the best nasin that was also uh studied uh it didn't work out on on outcomes on top of statins. It was the uh you know two studies aim high and the uh HPS Thrive trial both showed nasin on top of statins did not lower LDL so did not lower um events events.

uh the Thrive HBS2 trial there was uh it looked like if you looked at it uh in a another way to look at the analysis it did lower events by LDL lowering because it lowers LDL also so that was that was that was actually postcerop so tricep was the fizer CTP inhibitor so it was rushed into CL everyone was rushing to get a CTP inhibitor because it raised HDL you know 50 75% you know we thought we'd have the cure for heart disease because the HDL every every 1% increase in HDL and 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 you know I personally had a low HD I have a low HDL in my family. So it was like we were I was the actually I was the first one to patent C inhibition back in the in the 90s. I was the first one to file a patent on CTB inhibition. 1993 was the the patent was issued. So I I had a lot of hope that CT inhibition would be would be the the the end of heart disease.

So um so tricetrop was underway. They they rushed it even though they knew and I was I was involved in the first you know phase 2 trial that it raised blood pressure quite a bit. It was it wasn't clear how much but we we knew it raised blood pressure like three three points five points maybe. So it went into the um the big trials and uh unfortunately it was stopped due to increased mortality both cardiovascular and non-cardiovascular mortality. So it's a real a real big disappointment.

And do you think that that was attributed solely to the increase in blood pressure? It well the blood pressure increase actually was the uh was only the tip of the iceberg. The drug had a very prominent effect on increasing getting to the adrenal glands and would marketly increase eldoststerone and steroid production and so it was a it was just an offtarget effect. We know that because in animal model like the rat they would give tricetrop and the blood pressure would go up dramatically within within an hour without and has no they have no CTP the rat has no CTP.

So that said it's not it's an offtarget effect and and and since then there's been a lot of CTV inhibitors that have well let's let's say four. Yeah. So let let's take them in order though because the story is so interesting. So this was a big blow to Fizer. Um and it I don't remember so I'm curious what how it felt from the inside. Was that viewed as a shot across the bow that this drug that this target might be the wrong target or was it No, we realized immediately this was an offtarget effect.

It was just a bad drug and then because I think Merks Merc was next, correct? No, no. Uh Ro. Yeah. So, no, it was it was mostly offt target. That was everyone the the real obviously there were some that thought, okay, maybe the target's off, but but that that that that came later. more validation of the target actually came later as well that it is a valid target. Okay, I I can get into that but the but the uh initial thinking was that it could be well an offtarget effect and and FIS did a lot of work on understanding that others that followed could actually isolate the offtarget effect to a certain comp composition in the molecule itself.

I mean they knew wow the the the chain on toetrop that was the inducer of the eldoststerone secretion. You could you could you can do that in cell models. You can find you know what was the component that raised the eldoststerone. And they they they developed other CT inhibitors that lack that you know that that that component of the of the molecule. And so those were the next ones to follow. And then again it's all about HDL. Keep in mind it's all about HDL raising. No one's thinking about it for LDL lowering.

That's the that's the key thing. And but what was the thinking Michael? So why 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 did how was causality established as opposed to association? That's a great question, but there's a lot of work that went into the HDL function. You know, what does HDL do? So, HDL is a uh a lipoprotein that is um also you kind of made made by the liver and the intestines and it goes to different organs and it basically picks up cholesterol.

It it's eluxes cholesterol into the lipoprotein. It goes from an empty garbage truck to a loaded garbage truck and and an an empty pita pocket to a spherical how how you want to describe it. It's a and it matures. It goes from this this pancake up to a a big ball uh filled with cholesterol. And there's different enzymes along the way that that kind of help you know maturate the the particle. [snorts] And once the spherical particle is is mature, it goes to the liver and gets cleared.

And and and actually the predominant uh route mo most people don't realize this, but the majority of bile that the liver makes comes from HDL. H comes from HDL. That's the bile. It goes funneled more into the biliary system and then then out into the intestine. So HDL is the the precursor, but it has a lot of functions that are um really interesting. It it's a it's a uh it picks up a lot of garbage along the way. It picks up all these uh inflammatory components, the cytoines.

Um uh and it's like a dump truck. It's picking up stuff and it takes it back to the liver for for clearance. That's what that's what the purpose of it is. And and part of that is cholesterol. And so people thought it's going to the plaque. It's picking up cholesterol reverse we call it reverse cholesterol transport. and it it it picks up the the cholesterol and removes it from the plaque and that's why you get less heart disease with with HDL. So it was all mechanistically, you know, based on on that finding even though the amount of cholesterol that it got from the plaque was was actually minuscule.

Yeah. Minuscule and compared to what it does to other organs, but it but it's the um it's the vehicle for for cholesterol transport. Uh and it's also has other functions. It's very important in immune function and in trying to uh you know battle innate you know kind of pathogens and things like that. So it it has a lot of other important roles to play in human health but but that was the reason why we thought you know HDL being high was good uh and then it functioned by removing cholesterol from the artery wall and taking it back to liver for clearance and obviously things learned it's a lot more complicated than that but that that's was our thinking back in 2006 when tricep unfortunately um kind of failed and and just to be honest uh where I was I mean I was a big fan of torsetrop even though the blood pressure went up because the H still raising the magnitude of that benefit would be greater than a three point increase in blood.

So I was kind of thinking okay if any raises blood pressure a little bit it raised HDL you know 75% we we should get a net benefit but it turns out it was much more complicated than that as far as the side effect profile. Yeah. How much did HDL go up with torsetrop about 75%. Wow. So despite that it I mean that's just per that really tells you the offtarget effects were devastating right. Yes. Um did it have an effect on LDL very much? I don't remember.

About 15% 10 at most maybe 10 to 15% lower. It was more it was really not even something people even paid attention to the LDL effect. Okay. So then the RO compound comes along. Right. What was the story with that trial? It's a weak CTP inhibitor. They even called a CT modulator. A very safe drug. uh and it uh raised HDL 50 uh sorry 30% maybe maybe 40 in some trials and a much weaker uh HDL raising effect very no LDL effect uh so went into a large outcome study very safe you know no no issues it it reduced the risk of diabetes which we'll come to later that was one of the things about the HDL raising benefit that we can talk about reduced the risk of diabetes but had no Mace benefit did not cause any MACE benefit.

Major adverse cardiac events. You're right. Right. Major Right. Heart attack or stroke reduction was was was nothing. There was no benefit there. Not even a trend. It was just completely flat but but very safe. And so that was the second failure, you know, high-profile failure. Actually went to another trial later. Still still neutral. No, you no benefit on major adverse cardiac events. That's number two. Yeah. Yep. And then merc. Then then lily. Oh my gosh. Then lily, which was evacetrop. Now that one was a that one's a good molecule.

Uh it uh again very safe and was studied uh again it was a time when Lily did not have the resources it has now obviously and so they were trying to go fast like everyone was trying to go fast because again this was the you know could be a huge opportunity to reduce heart disease. So it's all about so they went into a study with acute coronary syndrome primarily and and they showed again um LDL lowering about 15 to 20% HDL raising again 75% or so a very good um HDL raising effect and [snorts] uh they they only went two years though uh post starting the trial and they stopped for futility for no benefit on on major adverse cardiac events and secondary prevention secondary prevention She was a high-risisk secondary prevention.

By the way, Michael, the first two studies were primary or second all secondary. These are all secondary prevention. Yeah. Yeah. So, what's important about that trial is Zetto, which is now a well-known like we use all the time, Zia for lowering LDL. They they also did an ACF, acute coronary syndrome trial, which was similar to what was done in the Accelerate trial, which is the Lily trial. So we we know that two years is too short because in a similar trial with a zettoime which is a wellproven LDLin drug it has b everyone recognizes the benefit of a zetto that it took more than two years for the lines to separate in other after two years their lines were uh there's no difference in in major adverse cardio but after two years they separated and so the similar would [snorts] would have happened we believe with u with evacetra pib and the acceler trial with repatha and prrowulin we did see benefit at about 2 years but but this was only a 15% LDL lowering.

Yeah. Yeah. Yeah. Yeah. Yeah. Okay. And and then and then even uh with um so it's also interesting in the um in the uh Odyssey outcome study which is the uh pryulin which is the other PCSCAT inhibitor. Um if you look at the populations that had LDLs uh below 100 which is what this they also didn't separate until after two years I mean so there's same with forier which one was more heavily no forier was uh was repath but which one was more heavily statinized I can't remember I thought for both but forier was not a coronary syndrome population that's it was a chronic stable they they send a separate coronary syndrome populations sometimes can be they're pretty sick and they get a lot of events and so you have to go longer to see the the benefit Are you saying that your view is maybe the lily study was stopped too soon?

It it was stopped for futility when it should have kept going and that was a big that was for us a big issue for uh our drug obetrop that was the hardest one to explain. And what were the features of the lily drug in terms of HDLC and LDLC uh kinetics lower lord about 15 to 20% and raised HDLC HDL again 75% or so. So it's a good and al but the thing is it it was safe. It actually had a total mortality benefit that was significant but it was not a m not a major adverse cardiac event benefit.

So the drug would never have been that was not the primary endpoint. That's interesting. It had an overall AC a all-c cause mortality benefit right and what was that what other causes was that attributed to? Well it was largely cardiovascular but it has some you know non-cardiovascular mortalities and cardiovascular mortality was almost significant. And then then there was there was a uh uh also some non-c cardiovascular benefit as well. So what um did they prespecify that they had to have an outcome at two years? Is that why they stopped it for a few?

Yeah, they they had they had prespecified that there would be an analysis at two years. I mean it's it's there were also some corporate issues involved. They were uh it was a big it was a tough time for Lily financially. You know it's very different than where they are today. uh but it was uh they had to make some quick decisions about prioritizing their pipeline. So as as big corporations go you you you have to make these decisions. So they had decided to cut the study short.

Got it. Um and um again HDL raising you would think would have a benefit already. So it was it was the LDL lowering wasn't really thought of as the the main mechanism there. Did that study show any improvement in diabetes? It did also. Yes. all all the CT inhibitors even toropib showed a diabetes benefit all of them. So this is again why we're focusing on that with um with obetrop [snorts] as well. [sighs] So the important study though was the merc study that that actually saved the class even though the drug itself uh didn't make it to market uh for different reasons.

It it was to Merk's credit. I mean, they started the trial again all about HDL, but when they saw what happened with um the Lily drug and detropib, they they wanted then to make sure the study was adequately powered to maybe pick up an LDL benefit. And so they they power they had 30,000 patients. That's that's perhaps the largest outcome study ever done. And they went for four years. So very large study. They went for four years. The baseline LDL was 60. So we're talking about already low LDL.

They got a 17% LDL lowering, 11 milligrams per deciliter, absolute LDL lowering. They got a 9% relative risk reduction, which is what you'd expect if if not more so what you'd expect. And so it proved the LDLing 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 compos deposition in fat tissue that wouldn't stop depositing. And so if you took it, you would not wash the drug out for years actually.

So there's also environmental issues. It gets in the water supply. There was just a lot of issues that MK would have to deal with with a drug with that type of pharmacinetic profile. And how did they figure that out only in the large phase three study without knowing it in say a phase two? Like what what was it that even brought that to their attention? Well, as as the studies went along and they started getting more um in the phase, you know, two studies, they didn't look at long-term, you know, kind of clearance of the drug.

They didn't, you know, it started they didn't do the PKs. They did the PK. They knew it was a long halflife. They didn't know realize how long. They didn't realize how long it uh how much it got deposited. We actually did I did some of them. You did actually did fat biopsies to see how much drug was in the fat tissue. And so that was the um And this was an oral drug. Oral drug. Profoundly hydrophilic, right? Lipophilic. Lipopilic. Lipophilic. Yes. Wow. Yeah. So it was unfortunate uh in that it was just not a viable commercial drug, you know, for that reason.

Even though it had good safety profile, it lowered mace. uh but also because the magnitude of the mace benefit was modest. People don't realize that that's an 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 the events, it was it was the a great study to it it confirmed that the LDL lowering with the CT inhibitor can in fact result in a cardiovascular benefit. And now you 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. Um when you line up all of the primary prevention trials full stop, all of the secondary prevention trials full stop, all of the mandelian 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. Right. Right. Right. So there are four distinct lines, different slopes based on different and therefore given how tight those regressions are, it becomes very uh easy to predict what you're getting at.

And that's that's what 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%, etc. Yeah, it's a wellnown it's the formula is easy. It's well well established for a um 1 mill mole which is 38.8 milligrams per deciliter of LDL you get a 22% melter risk reduction. Yeah. And that's largely linear. It's linear, right? It's absolute is is the key, not not percent.

So you you got to look at the absolute LDL lowering and then you can calculate the benefit. We and we're doing that for our obviously our outcome study. We we can have a predicted benefit based on our absolute LDL lowering that we hope to achieve in in our in our in our prevail trial. You can then you can power studies accordingly. You can see what the benefits as long as you go long enough too. That was the other key thing the in the first year of treatment you you get you get half the benefit at best.

It takes time for the lines to separate. Yeah. 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 Mandelian randomization says we're going to lower it genetically, right? It's the genetic lottery that determined your LDL versus mine. The primary and secondary prevention trials are based on a popery 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, you know, it's hard to deny that these drugs improve outcomes, but it must be something different than LDL lowering if you want to deny that LDL plays a role. They'll talk about pleotrophic effects of these drugs or things like that." But obviously those arguments become a little bit silly in the when you consider the totality of the evidence. Right. Right. I've never been a pleotropic. In fact, I was the one always debated that issue. I've always been it's LDL, it's it's LDL.

I mean and and you can now I think the argument is stronger that there's nothing special about statins other than they're you know very effective and well tolerated but there's nothing special about the LDLing about statins that result in a greater benefit than any other LDL drug that can achieve the same levels in a patient. So with all of that as um as background now let's talk about Obisetropib the work that you and John did how you know and the team of course but but let let's just talk about how you decided it was worth you know going after this for a fifth time right so uh so I had I had sold my previous company an interlucan 6 antibbody uh for heart disease inflammatory it's a I don't if you IL is six, but it's the the key inflammatory cytoine.

And that study is actually coming out this year. It's called the Zeus trial. It's a big big study coming up. So I I had sold Corvidia and John uh said, "Let's get let's get Obetropib back, you know, from Amgen. Uh Amgen had put it on the shelf uh because Rapatha uh had struggled on its launch and they they they depprioritized it. So they kind of had it sitting there ready to go into, you know, phase two, maybe maybe even right into phase three potentially. So we we uh teamed up together and started New Amsterdam Pharma.

How many years ago was it? This is five almost. This is our sixth year now. So So that's so interesting because Rapatha launches in 2015, right? It they kept Obi on the shelf for five years. I think they bought it in 2017. They bought it in 2017. Interesting. Yeah. But they did they they actually did a lot of great work on the manufacturing the process. They made a much more they worked on the made it much more coste effective manufacturer but they didn't do any clinical trials.

They just kept it on the shelf and sorry it already had an IND in the US or this had phase two data in the US. In the US. Yeah. Okay. It was ready to go. So we initially um you know thought about you know stat intolerance and using it for those patients uh as a quick route to the market um but we realized you know with the FDA view on on CD inhibition because of the history we really didn't have a path there FDA does not like statlerance as an indication.

They're they're very they're very wary of it even really being a true thing. Believe it or not I mean you and I I see it. I don't know if you we all see it but sure but no but but the the in the academic world and in the FDA it's they don't really believe it as a true phen because when you look at the placebo control trials it's it's very you know very low 4.9% is but even true statin tolerance is very hard to find I mean it's in the in the trials I mean it's but anyway it exists it exists but anyway that was our first uh path uh however once we met with the FDA and realized that we we we need to go uh into a full a full boat, you know, LDL lowering path, which is a much more larger program.

And so uh and also we we we we know we had to have outcome study uh at the time of the launch of the drug because of the histories we What were the phase 2 data that you had at the time of acquisition? We had a tulip study which was the uh done so that John had led uh in a predecessor. Yeah. Can you remind [clears throat] me and the listeners what that study? So it showed that 45% LDL lowering. Okay. So what was different about OB?

It's a much more potent. So it's only like the other the other CTM inhibitors are all in the the 100 mgram plus range and and they lowered LDL as I mentioned. And you're at 10 milligrams. They were 10 milligrams. even five milligrams we had initially too lowered LDL in that 40 40 to 45 to 50% range in the in the trials and so and the HDL raising 150% so it's a lot more effective on both lowering LDL and raising HDL so so it has it was just a much more potent CP inhibitor and the duration of the tulip study was how long it was just a short-term study I think it was 8 to 12 weeks something like that it was it was relatively short study Okay.

But it wor it was very effective, very well tolerated. Um and it was it was um you know a really nice LDL benefit. So we wanted to look at for LDL lowering. Again the meantime [snorts] all the mandelian randomization studies besides the merc data at the same time or roughly the same time [snorts] all the mandelian random emission study confirmed that CTP LDL lowering translates into cardiovascular benefit. Now weren't these the same studies? Sorry to interrupt, Michael. That suggested that the HDL raising had nothing to do with the benefit of CEP inhibition.

Right. Exactly. Yeah. And [clears throat] other HDL raising genes saw no benefit. At least the benefit could not be explained by the HDL effects. It was if you looked at HDL raising genes that are associated with lower risk, they also had other things like LDL lowering or triglyceride lowering. There was no pure HDL raising gene that was associated with protection. This was a this was a paper in nature circa. Yeah. What 2012ish? Yeah. Right. Exactly. That was years ago. So So it was so that was the other important I feel like that doesn't get enough attention because to your point you said look there are still a lot of doctors out there a lot of patients I hear saying well my my I hate the term but it's people know what I mean when I say this.

my good cholesterol is high, so I'm okay. Right? So, notwithstanding the nomenclature flub, even if they were to say my HDL cholesterol is high, I'm okay. The answer is no. We've known for over 10 years that that is not true. You notice I really worked hard to avoid saying the term good cholesterol. I I'm avoiding using that term because our mutual friend hates it as we know. But, uh but it's uh yeah, I it's the wrong way to phrase it. Yeah, it's the wrong way to phrase it, but but again, it's it's it's 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 I really struggle when I hear physicians say, "Yeah, but his HDL cholesterol is high, so we're okay, right?" You know, or I hear I have a patient that comes to me and their their LDLC 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 mean, I'm fine." Right. Right. Right. So there so HL is really interesting there we we believe it could still have some cardiovascular benefits if you raise it the right way.

Um and also because HDL's got there are definitely genetic factors that raise HL that increase risk like SRB1 for example that's a a known high HDL gene that that does increase risk. We know alcohol raises HDL and causes all kinds of higher uh mortality issues. So when you look at HDL, it's a it's a complicated thing to have a high HDL. You really need to we can 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.

Yeah. I have a friend with very high HDL cholesterol about 100 milligrams per deciliter and uh modest LDL cholesterol. So maybe also 100 110 milligrams per deciliter. Um, and he had always assumed he was totally risk-free. Uh, maybe his LDL was even lower than that. It might have been, you know, 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 probably is uh your HDL cholesterol is probably reflective of something good or protective.

Um but you know I've read enough cases in the literature to see that it we could be looking at highly dysfunctional HDLC. So would you mind uh getting a CT angiogram which he did and he had significant burden of disease. Yes. So he probably he probably has the SRB one. That's Ashkenazi Jewish predominantly. It's a uh that's where we find it most commonly. It's still relatively rare, but it's um but we see I have a a whole case series on that in my lipid clinic that have the high HDL due to SRB1 and there's anthe there's different like there's like three HDL raising genes that don't either don't protect or increase risk.

So it's and then you have alcohol. So you throw that in the mix, you get you get a very complicated story about HDL being high, being protective and and so but there are re the reasons to believe we we still have hope that that that that Obetib's HDL raising benefit can result in a cardiovascular benefit, but we're also focusing primarily on on what the other HDL benefits could be like like like we're still talking about later like diabetes prevention and Alzheimer's. That's what we hope is linked to the HDL raising benefit and we we like to we're investigating that now in our in our in all our studies.

So when John was on the podcast again I think it was four years agoish but um you know a lot has happened since then. So, so let's let's talk about where we are today where where are you, you know, what is the state of understanding of obese 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 in that order.

So let's start with what is known today based on the is the Rose trial is the most recent. Well no Broadway tandem. Yeah. Yeah. Those are all so we've now done um you know two more you know phase 2 trials in and three very large phase three trials and they're all been completed and were actually filed in Europe you know for approval in the US. We're waiting to time it on the outcome study called pro. So we started to prevail. We had the I I hope the courage and the foresight to start our alchemist study at the same time as our phase three trials as a small company we we able to knock on wood even though we'd have the money to finish the trials you know start the trials uh get them completed and then we raised money along the way to 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 the the success of the phase three trials allowed us to fund the finishing the other trial.

So it kind of timed it extremely well you know for for our our efforts. So um we had Rose and Rose 2 you know both showed the uh again the 45 to 50% you know monotherapy benefit and then uh in combination with the zettoide were you know in that you know 55% range higher you better LDL lowering. So then we um we then did you know uh the what was called Brooklyn which is a familiar hyper cholesterolmia trial. I know you've done multiple podcasts on this autotosomal dominant genic disorder.

You know, very high LDL, you know, showed a 40% LDL lowering over a year. So, it's a a one-year study. Tell me about those patients. They were already on all on maximal almost all were on high intensity stats. Many were on a zettoi or peskine inhibitors already. These were very well treated, but their LDLs were still too high. How high? The average LDL is roughly around 100 something like that. So, okay. So in other words, the inclusion criteria is not limited to exactly which drug you're on.

It's just that you're on maximum therapy and your LDL is still above a certain threshold. Right. And and so then we had did um so sorry adding so on the familial hyper cholesterolia patients when you show up at a LDLC of 100 on whatever com combination you're on obetrop lowered it by an additional 40%. So lowered it from 100 to 60 millig per deciliter approximately that was I think those those are approximate numbers about 40% was the reduction at the end of 12 months versus placebo versus placebo.

Yeah. Okay. Then and then the uh the Broadway trials are are other these are all um athoscorotic cardiovascular disease patients again all on maximal statins majority on highintensity statins like 70% were on you know 20 or 40 of 40 or 80 of a tovvis all are all very well treated uh and we got um you know roughly around around a 35% LDLing benefit um and then adjusting for placebo a little bit less than that but it was it was around that percent change at 12 weeks and then then continued for for 52 weeks.

Uh and so that was our two pivotal phase three trials and in combination with the zetami we did another trial called tandem where the audio lowering was was was very very much 50%. So we we have a combo pill we're developing the the two drugs together. What was the point about Broadway though that really helped us a lot was we showed in that study a uh a 21% reduction in in major adverse cardiac events in one year in one year. It was not simply significant because this is a you know it's 200 patients but but it was the right direction and it was pretty powerful.

We if you look at you know kind of a landmark analysis we divide take the first six months away it starts to become significant. So you remember it takes time for these curves to separate. So we um everyone got excited again we're trying to obviously leverage that with you know with prevail because it's almost identical population in prevail which is 9500 patients and it's a ASCVD athoscotic carvascular 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 unethic issues ethical issues so these are all on maxly tolerated stats that's called prevail and that study now is approaching uh in the in the year three of the study now and so we and this study will read out when well we're we're we're have two two factors to stop the trial one is that we have a minimum followup of two and a half years again the learnings from the from the other trials and the other is it has it's also event driven how many events the power of the study appropriately for for we call four-point mace which is you know the heart attack stroke cardiovascular coronary death and then revascularization coronary.

So those are the four-point mace. So we have that um events need to be adequate to you know stop the trial. So that may take us into a little bit longer than the 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 followup and that will be a trial evaluated in both Europe and the United States all over the world. Yeah. China, Japan, everywhere. There's 400s, you know, 400 plus sites and it's a global study and the outcome of that study should it be positive would be approval in Europe and North America for obese in secondary prevention.

Well, we we actually don't need it for approval in Europe. Uh why is that? Well, it's a different system. They they they they believe in LDL lowering is LDL lowering. So, you don't need they don't need the outcome trial. They don't need the outcome study for approval. Uh the US is different story. And then then then they have a year to set up their payer um mix. So they have the year for the outcome study to kind of come into the into the payer uh 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. Yeah. as the uh so so I went through the Rose 2 trial the other day and the one of the things that I found interesting was the 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 apo lowering I don't remember it was maybe 16% but it was it was much more modest than the others what do you think accounts for that it's something we're looking at you know, very careful.

I know, you know, a lot of our good friends, you know, Tom Allen, they're all APOB. I'm more of an LDLP person. Uh, for for a couple reasons. One, it's easier to get in our lab, you know, the Really? Yeah. Easier actually. APOB is still pretty easy, but I mean, I feel like APOB is the easiest thing to order. LDLP, but also LDLP to me is more commonly discordant than APO. can see it more easily because like apo LDL is 80, apo comes back 85. Is that is that really disc you know that kind of thing?

This if you have usually would typically have with LDLP you have LDL 70 LDL particles 1500. It's it's very easy to see the discordance a lot easier. Which assay did you use for NMR? This was the this is the liposcience liposcience one which is owned by LabCore now. It's owned by uh LabCore. Yes, [clears throat] this is Jim Cromwell's old assay, right? We actually actually No, we used the we we used Liposcience. Yes, that was the assay that we used. Okay. So, that is the most reliable one to my know, right?

Exactly. Right. And and so we we're doing a lot of work confirming that and Tom actually published a paper when LDLP and APOB are discording what what is driving that which is not very common but you do see it and is insulin resistance and a lot of small particles. you get discordance between APOB and and and LDLP. And then we there's a study done at the uh the C. Sorry, you said APOB and LDLP. Did you mean APOB and LDLC? No, LDL LDLP when they're discord.

In other words, when Apo is not high and LDLP is high, what what explains that? You know, what is the, you know, what is the reason why you have a a a normal APOB and a very high LDLP? But I don't understand why small particles would explain that discordance because each particle still has one apo on it. But it turns out the mass of apo is different by the size of slightly different from the from each particle. [snorts] That and that we believe is the explanation that we Why is that?

It's because when you have the the smaller surface that the the the masses is not just the protein there's also other um sugar molecules that attach to that that make the the mass of when you measure the so apo is a mass assay and the uh the LDLP is is is the NMR the nuclear magnet is resonance. So there is so CTP inhibition is the one example where they you get different results. I mean you get LDLP goes down very much dramatically. Small particles go down by 90%.

You wipe out small particles but 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 like the UK bio bank trying to see what when that happens you know where does risk follow. Exact. Well, that's 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, right?

And that and I know some people have brought that up as a as an issue, but you know, we feel, you know, John and I both feel very confident that it's going to be as good. Uh, and I think one one thing I think that we look at what's called non-HL cholesterol, which is very close to Apo B. It's it's LDL plus VLDLDL cholesterol. uh and we go back to the the uh the merc trial the reveal trial that showed the um the benefit there was driven it was really highly coated with non-HDL cholesterol more so than apo although there was that paper in either JAMAMA or New England Journal of Medicine about six years ago that compared apo to non LDL non HDL non HDLC and APOB performed better others have shown the opposite though I mean there's been it goes both ways you know so and I thought so I listen I love APO OB I always have and I like like LDL it's it's important to understand what discordance means and and discordance you can get discordance with using nonHTL APOB or LDLP I I think by and large they tell you the same thing um by and large I mean so um yeah this is a third order term I I think we we and if you if you're you know the cheap way is nonHDL then apo and LDLP are are other more maybe more a little bit more precise but you another lab test involved.

Uh but we we believe yes. So we're we're we 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. Uh but we do even do better if we use nonHDL. Uh but of course what Oetrop has that we're also excited about is the LPLA lowering benefit. Yeah. How much was that? That's about 50%. Which is more than a PCSK9 inhibitor. Right. Right. In in the 50 to 150 range. We have to you have to bl bracket it by the range of LPLA and so that's where and what do you think explains that mechanism of action?

We don't know for sure because we've been trying again we don't know why Piskan 9ine lower LPA we don't know the reasons all the reasons why um the those drugs lower LPA about about 15 to 20%. But we we were looking into this more. We we we have done a clearance study. It it does it does reduce um production of LPLA. We've done an actual assay looking at you know a study labeling LPA and seeing that it does reduce synthesis in that study. Um but um it was a small study so we we want to try to but we don't we don't necessarily have the all the reasons but alkalleing was seen with other CTV inhibitors as well but not nearly as much.

It was the same the same thing. You know, it's it's we have a much more potent CTV inhibitor. And and where are we right now with the anti-sense oligoucleotide that lowers LP little A? Is that that is still in a phase three trial? Yeah, it's coming out this year. It's called Horizon and uh it's a really important study. It's got although it was extended, it's extended. It could have been stopped for futility, right? It could have been stopped for futility. Um and it has a a lower than expected event rate which probably brings us to another important discussion about how do you treat a high LPLA today?

You know what what is the mechanism? So you want to bring the LDL down and then so they brought the LDL down to 60 in horizon. And so they had they had a lower event rate than expected. And so I think that that proves our what we're doing today because I I'm sure you hear it too, but when you when you have a patient who has high LPLA, they go, I don't want to be on a statin because it raises LPLA. And so what what do we do?

Well, the truth of mality is you bring the LDL down, you you you really mitigate risk substantially. And so that's what 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 the drug the ASO didn't didn't matter you no no I think it will matter but well it didn't matter in the time frame that they looked yeah but it also just need to collect enough events I mean it could well matter I mean it's and it's going to come out we we believe sometime this year has been been reported so that'll be that'll hopefully uh convert the LPA to our very opening discussion about causality that that becomes then yep 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 it'll be a great achieve. Now, this this may not be the best LPA lowering therapy by far. There's others that are look a lot better that are moving into big trials as well. And so, we're going to it's the LPLA uh kind of era is is getting started. I mean we're we're getting to another uh hopefully you know very important causal uh factor that can be treated aggressively with with therapy and we we we hope obese can be part of that you know part of that treatment paradigm.

So from a purely cardiovascular standpoint how do you see obese being used should the um outcome trial end in the fashion that you would expect? Where do you where do you think it fits into the current um you know toolkit we have with respect to pharmacologically lowering LDL? I want to say again your your your question is the right way to frame it. We 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 you know what statins do well and what they don't do so well.

So statins lower LDL and they're well tolerated and they and they uh reduce cardiovascular events and they're generic and they're they're very easy to treat. Yeah. Right. So that's all the good things. What does statins not do so well? It raises the risk of diabetes slightly. Um it raises the LPLA and it and it lower does not lower small particles very well. It lowers mostly the the non small particles. What does obetentropib do? Well, it lowers the risk of diabetes based on our our Broadway trial data as well as other CT inhibitors.

It lowers LPLA in that 50% range in that moderate band. And it um and and it lowers you I mentioned that it lowers the risk of diabetes, lowers LPA and lowers the small particles by 90%. And so it would be a great companion drug to statins. And so we we believe it becomes the go-to drug after statins for those reasons. It makes the it makes the the statin liability issues it mostly go away and that it really is a good companion drug to a statin for that reason.

Now we have the combo pill with the zettobe which puts us in the same range as the psychi inhibitors or or the or even the upcoming oral psy inhibitor. There there is another issue John with statins that I don't think gets enough attention because I realize it hasn't demonstrated a clinical um harm. But there's something that always and and I guess we just out of an abundance of caution pay attention to it which is it it can have a pretty significant impact on transaminases especially when combined with a zettoide.

Um and we see that I 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 a 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, you know, Crestor and Zedia walking around with A and ALT of 80. Right. Right. And the reality of it is I just have a hard time believing that that's that that makes sense.

What What's your view on that? Do you think I'm just being too Do you think I'm being too much of a Puritan? Not really. I I kind of feel the same way. You know, I'm a first do no harm kind of guy. I mean, but I do do bring up you bring up a a very big point for me in my in my clinical practice is I don't like highdose statins. I don't like 80 milligrams of a tobacan in particular. I don't like 40 milligrams of ruba.

Um I don't want Have you seen Tom Desping put out a beautiful figure from like he he's one of like your classic Tom figures that he pulled out of all the literature and it shows the dose response of every statin. And we now show it to our patients especially those that come in on highdose 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.

Yeah. I It's like the number needed to harm versus the number needed to treat benefit is just not not desirable, you know, for when you think about a high. So I don't I I try to cut the statin patients, by the way, they they don't want highdose statins either. So I think the whole the whole highdose statin kind of guideline paradigm is is off. It it doesn't work. Well, and and in defense of it, look, I I 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 proluent, you didn't have a zeetto, you didn't have bmpidoic acid, you didn't have c, you had nothing, right?

So, so if you you know, this was your drug. We didn't have evidence of benefit either on top of these drugs. And so that now we have many studies showing the benefits. I think we you can see the the the tide is turning. People are now advocating at guideline. Europe is already on board with more combo therapy early just to get combo therapy. So I think obicetropid then becomes in my view you know based on our data should become the next go-to drug and if you need even more potent you can add the zetto combo pill.

So we believe that with OB alone and OB with the zetto 90% of patients are done with their lipid treatment. And so that's how we think and that and that for primary care doctors that's what they're looking for. or they're they're looking for something they can just add to a statin and then they can call it a day. Why? Explain something to me. Um so if you go and buy branded Zedia today, it's not that expensive. If you go and buy branded Nexl, I mean it's as expensive as an injectable monoconal antibbody.

Yes. So do you and maybe you don't want to talk about this but but I have to ask. I mean when you think about how obetrop will be priced in the United States is it is it going to be priced more like Zedia or is it going to be priced more like Nexal? Unfortunately it's all about access not about price. That that's the big difference. Uh so we haven't decided on pricing. You don't do that till you till you launch. But I hate this. It's really unfortunately how the system works.

I mean, you you you if you price too low, the the the PBMs don't have any rebating uh profits to make, so they don't put it on formulary. And so, you you got to be able to play the the rebate game and price it accordingly. Now, we're starting to see that breakdown also with, you know, direct like Lily Direct and all these. So, we love to see that system get better uh as time goes on and so people can just pay a reasonable price out of pocket if they want to and and they get the drug.

Yeah. I mean, look, you don't you don't need advice from from a bonehead with a podcast, but I really think it is a terrible mistake when these drugs are priced outrageously. Well, we know Copatha was a huge example, right? I mean, what a blunder to price that drug at $16,000 per year. I mean they could have run rough shot over the market if they had just priced it within. Yeah. So so again I assuming that the results of prevail are as promising as uh they should be right.

You never know but they you know what they should be. Um it would do such a disservice to patients for this drug to be priced even at the level of of Nexl. Again Nexatl is an inaccessible drug. Yeah. It's it's a to me it's a donkey ass drug. $6,000 a year for that drug. It's just not worth it. That's why we have a hard time finding a place for it for that reason in the clinic. It It's really limited the stat intolerant patients that don't want to take an injection.

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

Sure. Yeah, really it's a it's a very exciting for me to talk about it because that was one of when I came to New Amsterdam with John, you know, John said, uh, you know, Michael, I want to hear your story about Alzheimer's. And I said, let let me go through it with you because we had what we had at the time was a um uh mandelian minimization. We had the the famous, you know, Bronx aging study where people who uh 400 Ashkanazi Jews uh over close to 100 or older uh had uh 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 CT loss of function your your your risk of Alzheimer's is significantly mitigated. So we had genomics validation. What was the phenotype lipid-wise of those patients? Well, they have high HDL. I see. So these are these are APOE E4 patients who phenotypically have very favorable lipid profiles, but until you do the genetics, you wouldn't know it's due to and they have very low small LDL and they have very high large LDL particles.

I mean, it's just what CTP inhibition does. Michael, what was the degree of risk reduction in those APOE E4 patients? Well, you look at the curves, it it basically took the E4 risk away. That was, you know, again, this is one study. Um, and so they basically became the the risk of a non-E4 by having the CTP loss of function. Wow. So, that's a profound benefit. Uh, and um, so that's one. Then it's been validated by other other genomic studies since then that that we've done a lot of work ourselves on the but also in Canada at McGill a PhD researcher had done some really great work on CTP.

So you remember the mouse does not have CTP. When you give the mouse the uh amaloid precursor protein gene they get they get amaloid and and dementia and then when you give them the CTP gene with it gets a lot worse. Uh, and then if you give the the mouse a CTV inhibitor, you improve the dementia in that animal model. So they they do nesting. They Yeah. So wait, wait, I'm a bit confused. You're saying you take a mouse that doesn't have CAP and you give it a CEP inhibitor, right?

Why would that change anything if they don't have it in the first place? You you gave the CTP. You gave them CTP. I got it. Okay. You gave the mouse the CTP gene. Yep. Then you then you block it. Then you say for giving CTB first of all made it made the dimension unders worse and then you gave the block CT inhibitor it blocked it. So we had 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 to look it out because unfortunately uh in the biotech world Alzheimer's does not uh it's a big a huge graveyard.

Yeah. And it's really hard to get funding for Alzheimer's studies. Uh but we had another obviously the LDL and the cardiovascular. So we we raised $200 million in our series A. We got 1 million allocated for Alzheimer's research at the beginning. So um that was what we had. When did you go public? 2022. Yeah. So we started a company in in uh 2020 21 early 21. started the the funding and then we went public in the end of 22. So um so the uh so that was the basis of our of our uh we had the the genomic data we had the uh 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 not not whole entirely convincing but number of studies showed HDL highest gel was protective against Alzheimer's especially APO1 which is the protein carrier uh for HDL. So that's that's where we started. And so then we uh with our funding we were able to do a small study uh in um in Amsterdam where we looked at uh about 13 APOE4 with in compared cognitive function mild cognitive impairment. We gave him Oetetropib [snorts] and we saw um uh some improvements in lipid metabolism.

So let me go let me Apo4 by the way is a lipid gene and so yeah that's a that's a fair point actually. Let's back up a little bit. talk about what about 8.4 is is detrimental. I mean that that's the key because when you talk about where does obetentrop fit in you know we have the the LPLA we have the the diabetes benefit the small particles but also the fourth leg of that is if you're APOE4 you also have high LDL as well and and lower HDL so it becomes another good drug to consider you know for your AP this that's 25% of the population so you can see where becomes a really good add-on on the statin option if you have any of those characteristics.

Yeah. Let's talk about the homozygous E4 patient. So what is happening in their brain as a result of the homozygosity those those that because again it's a it's a very subtle change in their AOE protein due to that uh that gene and how does it manifest itself in the brain cholesterol metabolism wise. Right. Right. So yeah, it's very complicated and and everything I'm saying is is is still you know there's still a lot of gaps in our knowledge about you know what exactly happens with AOA4 but the brain first of all the brain is a very cholesterol rich organ.

Um if you look at I don't hold me to exact numbers but you know 2% of the dry weight of the brain is is represents 50% of your body cholesterol and so you have tremendous amount of cholesterol in the brain and um and then you have a lot of fat you know mostly you know DHA a lot so fat and cholesterol make up a big big part of the brain uh mass I mean it's a big big part of what the brain is all about and uh and cholesterol is synthesized very avidly by the the neurons during your childhood growth phase and then after you become adults the neurons stop making cholesterol and and and myelin by the way is is is 50% cholesterol.

So a lot a lot of cholesterol goes into making myelin and then aststerytes uh are involved in um making they they continue to make cholesterol and they they're there to help kind of repair uh neurons and and also they're they're like the uh neurons are the are the uh wiring and the make the thinking and all that stuff that brain function does. But the eststerittes are involved in the nourishment and the garbage collection all that stuff that that are um that are involved in maintaining normal brain homeostasis.

Now the complicating thing is the bloodb brain barrier completely separates off the brain lipid metabolism from the from the rest of the body. There's no apo in the brain. There's no apo. It's all apoe and HDL in the brain. there's no uh and and there there's there's no connection between LDL uh in the plasma and LDL. There's no LDL in in the brain. And so 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 and you your APOE4 uh before the donor and you and you give a somebody an ApoE3 liver, they they still have ApoE4 in the brain. There's no there's the the brain stays whatever. There's no connection. No, I had never even thought of that, Michael. Yeah. So that's the uh connection. So there's no Do you think there's any clinical significance to that in organ transplant? Well, I I I mean, in other words, if you you can't So, the question is, you know, with with gene therapy now with if you could convert someone from a E4 to an E3, can you can you do it in the liver and correct the the risk for?

We don't think so. That's where that's where we don't know. We're still it's still a thought, I think. Super interesting. Yeah. So, APOE four, which is this you you basically there's a two, three, and four. or most people are 33 threes. Um there's about 20 25% are 3 fours and um and then about 2% so 3 to% are homozygote E4s. So E4s your homoy about 10 times risk of Alzheimer's. The 34 is about three times risk. 33s are average. And if you're two which is the best uh your risk is lower uh and you have longevity.

It's it's one of the best longevity genes to be an APOE2. So that's the um the breakdown. So, so when you have APOE4, what happens? This made so APO is made by the aststerytes and and they it appears that they have impaired cholesterol um elux and and lipidation when you have APOE4 and so the the neurons don't get the same nourishment or they can't clear cholesterol. becomes toxic and once cholesterol becomes toxic it can be there's one something called 24 hydroxy cholesterol which can be can go through the bloodb brain barrier uh 247 another cholesterol so the bloodb brain barrier uh it protects all that but there's one cholesterol that goes through it's 24 hydroxy or 27 hydroxy they can they can transverse the bloodb brain barrier so the the APOE4 patients have impaired clearance of cholesterol and Then that sets up a a toxic situation where it gets inflammatory and then amoid and tal follow.

And so when Alois Alzheimer's, you know, first described Alzheimer's, it was amaloid plaques, you know, towel tangles and basically lipid deposits, you know, that was the and so when you have APO4, you can't clear those the lipid as well. uh and and that that sets up the whole Alzheimer's uh cascade and then they get Alzheimer's, you know, roughly, you know, one4 gives you Alzheimer's about 10 years earlier. So, and then two two fours 20 years earlier, that kind of thing. So, it's a a very um wellestablished risk having the APOE4 uh genotype.

Um so that's that's the background about APOE4 and it's a lipid gene and what what is important about obetropib is that we have that genomic data we had the animal data uh and then we we know that HDL is the one lipoprotein that does interface with the brain it's it we we're not positive we don't think 8.1 is actually made in the brain comes from the periphery 8.1 being the protein car I thought it was made in the liver you're saying if the brain brains APO A1 is made in the brain or made in the liver.

The li most of it we believe comes from the uh from the from HDL from the plasma not from the not so from the brain. Yeah, it may be made in the brain but we don't think so. We think it it it's made it and comes across the blood brain barrier. And so we know that for sure in the coral plexus which is the the blood brain barrier interface that and this is just mechanical. I mean it's because it's because HDLs are so much smaller than LDLs, right?

small HDLs and but SRB1 which is the receptor for we talked about that is is is heavily in the in the bloodb brain barrier and the cordal plexus. So the only thing that really interfaces with the the uh the brain from the from the outside the brain is HDL and so having high HDL um can help remove the excess um cholesterol that a4s can't metabolize effectively. [snorts] uh and also we we we prove this it it it delivers antioxidants to the brain very very important reduc the inflammatory response so we know we know we know that and also maybe DHA even can be delivered by HDL uh but certainly it's it's acting like it does it's it's the it's the removal system amaloid even amaloid can be removed by HDL so we believe that the HDL going up and interfacing with the brain can help mitigate the AP4 related uh Alzheimer's risk and that's that's what we What about in the non-fors do we have we think it's the same true I mean even obviously non-forsers get Alzheimer's and so but it's later it's it's later in life it's late 80s or 90s instead of instead of 70s you know 60s or 70s even so it it it's um we think of the same things are happening you know because you again you stop [snorts] you stop making cholesterol in the neurons you your neurons are dependent on on aststerite right cholesterol function and and and so forth.

And as you get older, you know, these things, you know, tend to get less effective. So we think that that that part, you know, we think could also be mitigated by by raising HL through obetrops mechanism of action. And what do you say to folks who say, well, 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 bloodb brain barrier, shouldn't statins, even though the clinical trials would suggest the opposite like just on an individual basis, is there some risk that statins would be driving Alzheimer's disease?

Well, I mean I mean just the opposite actually. I mean that the thing is we think that yeah I guess my question sorry should be why do we not see that? Why do we see the opposite in the clinical trials about about not not protecting against Alzheimer's? Why do we see that statins protect against Alzheimer's disease when you could argue mechanistically, but if they're lowering cholesterol and they make it into the brain? Yeah, that's we we're not sure. I mean, the big study statin trial that looked at Alzheimer's didn't show a benefit.

It did not work. That's not necessarily means that statins can't pro protect against Alzheimer's, which I think they potentially can. Um, but uh in the study that was done actually done, it didn't work. Yeah, it was a wash. It it didn't didn't work. Yeah. So, but in a [snorts] recent study analysis, they they showed that if you did have April 4 and took a stan, your dementia risk was lower. But that's an observational study and that's Yeah, I think that's fraught with issues. I I prefer these secondary analyses on randomized control trials at least.

Yeah. So, but but for the people ask about this all the time and you can say at least, you know, based on observational data, there's no increased risk of Alzheimer's. I did. First of all, I just want to get them over the hump. That's not that's not going to increase the risk of dementia because you hear that you hear that. I mean, so we we really focus on that protection issue. It's a hard cell to say it actually prevents against Alzheimer's because we don't think it it gets to the core reason.

it can't affect the the lipid metabolism in the brain the way obese potentially can because it it it's 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 louisibody 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 disease specific or not you know pathology specific do you think that's a potential I mean LDL is a dementia risk factor I mean that but it might not be an Alzheimer's risk factor through this mechanism it's a stroke you know benefit so we think that obviously elbetropib having LDL lowering can benefit stroke uh but also we do believe or hope that we can show u an Alzheimer's prevention benefit uh with our uh what we we we have already I we'll talk about what we showed already but we we were we're playing another study to look at it more carefully this year to to look at the uh the [snorts] benefit of obetrop on on prevention of Alzheimer's.

So let's talk a little bit about what you saw in your biomarkers to kind of validate all of these hypotheses. Sure. So we in so we got the first study that was a pilot study uh showed that we did in fact reduce um 24 hydroxy and 247 the the the steriles in the in the CSF went down did not see that you not seen that with statins so it was a difference and sorry how did you did you CSF CSF okay right we we measured CSF in these patients and we saw that the 24 and 27 hydroxy went down we saw stabilization of of um of biomarkers and we saw uh cognition stable.

We also saw had a few anecdotal uh cases of patients really having quite a beneficial effect on cognition but it was it was a pilot study you know was not power open label but we saw target engagement with 24 and 27 hydroxy going down. We also another analysis showed antioxidants in the CSF going up. So we we believe we had target engagement that we are in fact removing [snorts] these these potentially toxic steriles and improving antioxidant levels uh in the CSF. So that's a um that was the proof of concept study that we did.

And sorry what tell me about those patients. Did you say those had MCI? MCI all had MCI. Yeah. And just explain to folks clinically how patients with MCI would be behaving. So they they have um uh they do a cognitive testing and so they and they they have uh there's all different types of scoring systems but when you do the memory testing and functional testing uh they they score showing they have impairment. Um but what's important about Alzheimer's and why we're focusing on it is that um what we're learning now the the abnormality starts like 20 years before there's even MCI there's a long lag period between uh when we start seeing the pathology the amaloid and the towel and all the biomarkers going up and and actual MCI and MCI of course then has different levels until you get to the functional impairment where you're now, you know, it's not just this.

This is actually subjective cognitive impairment where people think uh they have impairment, but when they do the testing, they're they're pretty they're they're still pretty okay. And then you have those that are truly Yeah. you cognitively impaired. Yeah. So, so just so folks understand what we're talking about here, which is um Alzheimer's is not a disease of old age. It's a disease of middle age that presents in old age. And that's exactly what you just said in a different way. Um, so I I mean that's in some ways a frightening thing to think about, but it's it's just the reality of the disease and it also speaks to the lens through which we want to consider prevention.

Um, I would argue the same is true of cardiovascular disease. It's a disease not 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 um it starts effectively the moment you've got these LDL particles circulating. And so um what would you say is the canary in the coal mine? Would you say it is the that is measurable? I should clarify that. Would you say that it is the presence of of ptow?

Yeah. Okay. That's what's exciting about the field right now in my I like I said I came from the LDL kind of world. You know LDL became a great uh causal we I was when I was involved they weren't even sure LDL was really treatable. you know, when I started, I mean, they weren't even sure that you could reduce LDL and prevent heart disease. So, that we're talking about in the in the in the 80s. Yeah. I mean, so, so then for and then I mentioned already once you already have heart failure, you can't really lowering LDL doesn't seem to matter anymore.

So, the I think and 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 uh has shrunk and you got neuro degeneration. And so I think we're way too late in how do we treat Alzheimer's. So if we can find a prevention therapy and do you think that's why your statement earlier about how much this is a graveyard for pharma is basically the case which is on the one hand it's very difficult to develop drugs for primary prevention because the trials would take too long.

So you have to treat an active disease. But in this particular disease, if you treat the disease as dementia, you're hosed. It's almost like had cardiologists had the misfortune of trying to use lipid-linging therapy to treat heart failure, we may never have developed lipid lowering drugs. That's right. In fact, if they would have started with heart failure would all been failures. Frankly, we we did heart failure trials and didn't work. I mean, so with statins. Yeah. 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, right? And yeah, so it's a very unfortunate consequence of the pathology, though an understandable mistake on the part of pharma because that's the that's the hand you're dealt. have to you have to do clinical trials, right?

And I and I hope that like ptal 217 which is what we found in our can ultimately become a biioarker for regulatory approval. It's just we're not there yet. Uh but how does it differ from PAL 181 and I mean 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 PTA versus AB4240 and some of the other biomarkers that are becoming more common now. Sure. Sure. Yes. So a little bit of a kind of a background on on these on these biomarkers.

So they're all when we did our first pilot study the pile 217 wasn't available. So we we had we had 181, we had other ones. So then we did our we had a we we convened a big uh advisory board of e Alzheimer's experts. You I'm not I'm not an Alzheimer's expert. I I I I'm trying to become one now, of course, with all been but but the the um the panel said this new biomarker called PAL 217. If you can show over a year with our existing study with in Broadway that you're reducing pal, that would be a a great kind of validation that what you saw in your pilot study is truly an effect.

And so we that's what we did. Uh but but there is there is a so pal 181 and 217 are both towel measurements, but they correlate with amaloid in the brain. They're they're big they're very very strong predictors of amaloid on PET. And so if you look at centaloids of amaloid which is the the stuff in the brain uh with amal the protein aggregates and so forth and misfoldings the amaloid uh tal 217 and 181 uh predict that very well. I mean uh and and in fact in some ways I think the pet could be archaic relatively soon based on these on these biomarkers.

That's a big deal given the radiation and the cost associated with those. Right. I think they're it looks like from my look at the literature I mean they're as good as the PET almost on area under the curve for so they're very good at predicting uh amaloid in the on the PET. Uh they're very good at predicting progression of disease uh from normal to MCI. They're very good looking at MCI to full you know blown you know stage two or three Alzheimer's. And even progression of Alzheimer's is also uh predicted by PTAL 217.

So PAL 217 uh occurs a little bit earlier than 281. So it's a little bit earlier in the process. So it picks up earlier. There's also a new one called brain derived PAL which is maybe even better but still that's still early. So that's a towel. So remember it's amaloid first and then and then tal. And there's this conversion of amaloid to talopathy which is a critical transition in the disease process where the amaloid is that stuff and then tal itself is the one that really drives the neuro degeneration that occurs uh later.

So it's a it's first amaloid then a lot of tal and then you're basically unfortunately it's it's too late. PETA 217 is not a clea approved assay is it? Well, this 217 uh yes it is clear and but but it's divided by uh amaloid uh 40 amaloid 40 uh amaloid aba 40 as a that got approved this past year. So sorry you mean the ratio of pal to amalloid is is approved. It is approved. Yeah. Okay. So AB4240 is clea approved by itself, right? PL 181 is clea approved by itself?

Yeah, it's if it's not approved already, it's it'll soon be approved. It's being used. It's being used a lot. 217 not by itself, but in ratio isn't approved. Right. Right. Okay. And do you think that the ratio of PA27 to AB4240 offers a benefit over PAL by itself? Well, the data is is actually kind of mixed. I mean, the actually pal 217 alone looks awfully good. I mean whether the ratio is better I I I' I've never So you guys did your own assay for that?

Yeah, we we use quant we use the standard assay for P2A 217. So it's it was a it's called it's quantics which is one of the standard ones. So it was something called precivity which does you know the pal 217 with a beta 4240 but we looked at all the biomarkers. We looked at pile 217 pile 181. We looked at GFAP which is I I call it gal factor activation protein. It's not the right name. It's gal fibrillary acidic protein. It's it's a galactating biioarker. Uh also very good at early disease protection.

And then we had um the ratio 4240 ratio and the no filament light which is a a later stage you know kind of inflam inflammatory uh biioarker more when you see a lot in injuries but as well as you know multiple sclerosis or or ALS those kind of things but but it's in Alzheimer's too but late but later in Alzheimer's. So we had our whole study broadweight 2500 patients and we had a a sample that we could uh do it was prespecified analysis. We did analysis at the beginning and then 12 months at the end of all these biomarkers with PEL 217 being our the critical one to uh to look at and um we found that overall there was a reduction in pt 217 going up uh in the in the overall population.

Um, but which is I think is most exciting is that if you look at who we were worried about the most was it we had a population of heart disease patients that we're we're not that old. The average age was 65. Are we going to really see anything in a year? Because if you know the the data on these biomarkers, it takes many years for these things to transition into something, you know, really advanced. And so that's the key. But even low levels of these biomarkers can are really very predictive of future Alzheimer's risk.

And so what we found was overall it worked. But if you looked at people that were older, it it worked even better. If you looked at people that are E4, uh it it worked even better. And if they were 44 homozygots, we saw this profound benefit on on not just pile 217 over 20% difference from placebo. But all the biomarkers improved 181, amaloid 4240, GFAP, neuropilament light all got better with obese and that's what we published in our in our paper. So we felt that this this data really confirmed that obese was in fact active in you know potentially you know preventing Alzheimer's disease.

Now, how do we know how to interpret whether those will end up being I mean maybe the answer is we don't but um 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 you know hope that that alone prevents even the development of the pathology.

It's a really great question because the answer is I don't know what we're hoping that the field is evolving and we and the regulators have to help out here because right now PTA 217 cannot be a a an endpoint for regulatory approval. It does require you know improvement in cognition uh which which might be an impossible thing to show uh unless you like we unless you took for decade you know decades. So but what we're what we what we can say is that for us you know we're we're going to go ahead with another study.

Uh we do we do know that um the APOE E4 community, you know, there's a there's a new alliance of patients out there that are advocating for, you know, for uh treatment. It's like any genetic disorder. There's, you know, there's there's um they don't they [snorts] don't want to wait 10 years. They want something now uh for for treatment. But don't you think it'll just be used off label for that reason anyway? Well, we we we you can't you know, we can't unfortunately. I mean you you have nothing to do with that but I'm just saying like the 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 you know 20 to 30%.

Now we have no idea if lowering it 20 to 30% mattered but but it seems that it's not unheard of for people to take offtarget use. There are plenty of people using GLP1 agonist today for neurop protection even though that would still be considered sort of off label as well. Yeah, I mean unfortunately I can't talk about that as a CEO of a biotech company about off label off label use. But I think the um the the key is that I think ptal 217 with enough um advocacy you know can become a regulatory endpoint um for this reason.

I mean it's so good. I mean it's such a good but let's take the flip side of that. The you know the fineman argument that in science the easiest person to fool is yourself. Yeah. and 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 if what would be the the case for PAU ultimately does not translate to clinical benefit? What would be true if that were if we 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? Well, like you said, I like you have you have you're proving a biomarker, but you're not treating the underlying disease. you know that would be the but but it is the disease I mean that's it's P it's the actual towel that's in the brain that leaks out into the plasma so it is a me if you're if you're using these anti-amaloid antibodies or now they're working on antiital antibodies to and they're still got a ways to go uh obviously those anti-amaloid antibodies um you have some very modest benefit but not for APOE4 homozygot so I do feel that um the homoygot in particular which are the ones that we 100% go on to get Alzheimer's if they live long enough.

We we should hope that we could get like even like a lot of other rare diseases allow these surrogates uh to get approval, you know, based on a on a surrogate that which may or may not translate to a a clinical benefit. Yeah. I'm thinking less of it from a regulatory question and more just from a a biologic question of it's easy to get fooled, right? I mean, we're all we can all be fooled. I mean, HDL fooled everybody for decades, right? Yeah. For decades, people were chasing the wrong thing and they had all the epidemiology to back it up.

Um, but at the end of the day, it didn't matter. And so, I just I just I'm 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 PTA thing that took us down a rabbit hole. What a waste of time and money that was. We didn't save a single life.

I wonder what the story would be. What would be the revisionist explanation of that? Here's what I'm also say. In the last few months, there's been some supportive data that came out that's helpful. one one is the GLP-1 trials the uh a voke and evoke plus and no improvement in cognition no effect on ptal 217 on the other hand the trailblazer anti-amaloid trials Lily showed a pretty high a high correlation between improvement in cognition and pile 217 going down. So we have we're getting more data and we're going to do our own study.

We are going to do a study uh with 300 patients that have um pre-alzheimer's you want to call it you know not they have evidence of higher tow levels based on their APOE with MCI no not yet we want to get it before I said we think MCI is too late okay uh and so we got to get it before MCI MCI is like early heart failure right right exactly you already have nerve degeneration we know the brain is already shrunk and and all that stuff inflam inflammation is set in the cascades, the talopathy is already well underway.

So we can't I don't think we can I don't think you can wait that long and and hope but we can hopefully show that with our next study we uh prove that we confirm all this you know we want to confirm we you even though it was it was not a a prospective trial it was a prespecified analysis we confirm all this especially in the APOE4 homozygous patients the profound benefit because what we got most feedback from was it's just the state is just too good to be true I mean how how can this be True.

Uh and so we well it wasn't only 30 patients. I mean it had homozygote E4 just the kind but it was so cisly significant it was uh it was well accepted for publication and all that kind of stuff. So the question is what do we need to do to convince people that this is but right now the world the am the the Alzheimer's world is very fixated on amaloid. Laura, I'm actually I mean I am surprised to hear that, Michael, given the number of uh the bullet holes that have been fired through so much of that, right?

I mean, including some of the fraudulent work that was done, you know, in the in the last decade on this front. Why why do you think that that's they're still clinging so hard to that story? It's all about hope, you know, you got something that Yeah, it's all about because it's such a devastating disease and and but I listen I I I don't want to comment on the anti-amaloid drugs because it looks like some of the data might be encouraging, but it is it is a tough cell even you gota you got to take it.

You got to worry about brain bleeding and all that kind of stuff. It doesn't work on homozygote E4 either because of ara or just ara I'm talking about or does no doesn't work as well on the cognition improvement. I mean that's and you have the higher risk of they don't give it supposed to be kind of a contraindication to use it in E4 homozygote. So I listen I don't want I don't know if if um but but that could be the same question. Is it that antiamoid drugs could be beneficial but they have to be started 20 years sooner and that's what they're trying to do.

I mean they're trying to go earlier. I don't know if it's early enough is the question. you know, can you really convince somebody who's 40 years old, whatever it is, to to to take an infusion to prevent amalloid, especially if the side effects are potentially catastrophic. Right. Right. So, that's going to be a tough cell. Yeah. So I don't So we're trying to find like over six trying to pick like maybe age 60 we could find the right population because we know from our Broadway data who are the rapid more rapid progressors the who who who does t go up the most in and it is obviously E4 is older even metabolic even the diabetes that makes the the amaloid but so I think that um we we we we'll do another study and then that hopefully that'll set the stage for a phase three trial where we could look at conversion of normal to MCI by preventing that conversion and that'll be our next that'll be a long-term study uh that we hope to do, you know, pending results of the next trial.

Well, this is incredibly exciting. So, again, the hope here would be that we see um we see approval uh 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. Um, and this would make it a first, right? There would be no approved drug out there for AD prevention, right? Um, yeah, there's so much more we could talk about on this. Let but I do want to spend time on a topic that um we we you know we talk about from time to time but I have a feeling you're going to add a lot of value to my uh somewhat limited knowledge which is is the the most up-to-date thinking on the role of uh fish oils DHA and EPA.

You want to talk about it through cardiovascular disease first or talk about it through uh Alzheimer's or both or however you want to talk. I think the cardiovascular part uh well I'll get that I think my quick answer to that because I was involved in developing a omega-3 for heart disease called epova. We went to an outcome study and it it didn't work but it was DHA and EPA but mostly EPA had some DHA and that was four grams. How much? It was four grams. Yeah.

It was called the strength trial. Um, I think I think what I learned if I if I because I've always been a big advocate for omega-3s for triglyceride lowering and but but 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, you know, pathway and has like a anti-thrombotic effect, anti-inflammatory effect. And so there's really two reasons to think why omega-3s could lower risk. And one was through the EPA anti-throotic effect.

The other is triglyceride lowering. And so what strength was set up to do was really a triglyceride lowering trial. And it it it didn't work overall. There was a a hint of benefit in the secondary prevention arm. It was 50/50 primary. If I had to do it all over again, I would have made it all secondary just like the mostly the reduced trial was, which is the EPA only trial. So, the research trial showed a benefit and it it could have been uh it likely had some effects of the mineral oil placebo kind of tilt tilting it a little bit.

Yeah. Say more. I've heard this explanation before, but say say a little bit more about why mineral oil as a placebo could have been harmful. But you actually look at the inflammatory signaling increased inflammation. So it had some inflammatory Paul Ridker helped anal 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%, you know, so 9 to 10%. But nevertheless, I think I think it showed that EPA works. EPA works. It may not have been the 25% that people think it was, but it still worked.

It even you take all that away, it still worked. EPA only worked. Uh and then the strength trial didn't work overall. It may have worked more on the second it may have worked on secondary prevention in a in a post you know not post hawk but in that in that population and the placebo in strength was what was corn oil I see. Yeah. Just so folks understand what we're talking about here, in the EPA only trial, the placebo is mineral oil, but the the hypothesis was that the mineral oil itself probably increased events slightly, which made the EPA look better alone than it than it might have been.

But in the combined um trial, the DHA the DHA EPA trial, the placebo was corn oil inert. Yeah. And you're doing apples to apples. Yeah, corn oil might have its own. We had a hard time coming up with a placebo because it's not easy to find an oil placebo. Mineral oil has that advance. I mean it is it isn't truly inert but it does have that intestinal effects. Yeah. So this I I I think the mineral oil uh controversy is um it still I still think reduces shows a benefit for pure EPA.

Now the qu now then we had the prominent study which is a triglycerin trial with a fibrate pimo fibrate showed no benefit. It's very similar to the strength trial. Yep. population. Uh and so what that says is that EPA does work on reducing events but not through triglycerid for triglycerid. It's more for the anti-therotic 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 show much you've had you've had seen here and he's talked a lot about but APO4 people one of the other things is they don't they don't they don't get as much DHA to the brain they have a true you know DHA deficiency in the brain to some degree but really a new discovery which is very exciting is the MFSDA2 transporter MFSDA2 transporter. Uh, it's a transporter across the bloodb brain barrier for DHA.

It turns out that DHA prefers the lysopc form, the lysophosylcholine form of DHA. That's what the sub that's the preferred substrate for DHA to cross the bloodb 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 we're going to be as part of Jocasta we can we're going to be doing studies with lysopc DHA on showing it getting across the bloodb brain barrier completely independent of the cloth at work. Right. Exactly.

Yeah. So um so that's so that's excit that's that's coming and I I been in omega-3 one of the things that really until this receptor was identified we couldn't understand why you know why DHA doesn't get you know in into the blood brain barrier like you think it because it it does have to you don't you can't there's most of your DHA has to come from the blood has to get there it has to get there you don't your brain cannot make that much DHA from other fatty acids uh if at all I mean I think it can make some but um but but you you have to get DHA from the from the periphery across the blood.

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%. Right. And they were to supplement with a very high quality uh over-the-counter EPA and DHA um and they were to get that to 10%. Right? 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 because you can't you have to get the lysopc form to get to the brain and you have very limited capacity to convert that into the lysopc form until yeah another so you have to make this lysopc form which you can do with either a fishbased oil or a krillbased oil you can make lysopca so that's the hopeful uh excitement around the DHA and brain health that I think needs to be further.

But there is no version of that on the market today. It's coming. It's coming. Yeah. Yeah. But but will it be a drug or will it be a supplement? There'll be it'll be a dietary supplement. Yeah. Do you know who's making that? Well, there's a bunch of people making one's Well, one is already available krill oil based, but there's one with fish oil based coming. Yeah. So, and Jocasta, we're we're going to do the science behind that as well. For a drug or for a supplement?

For a supplement. Yeah. Okay. Um, you've been involved in so many clinical trials over the course of your your life and there's so much discussion about AI and medicine and the impacts it can have. But I 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 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 you know I mean frankly if you could take it to 400 million right so um and if you could take it from 10 years to one year I mean you would you could change the course of 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.

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

Yeah. So in other words make the efficacy not based on intention to treat but on actual compliance. Right. And that would be a huge difference already because we we your your effects are diluted so much by especially for long studies you have to drop in drop. So you can use AI modeling even to show that those who took the drug took it the right way the benefit was worked well. When you look at a trial like either Broadway or Rose 2, what was what percentage of the patients enrolled in those trials do you believe were nearly 100% compliant?

we we actually there's what's called on treatment analysis or um or you know kind of looking at PK you know who who has the right take of the right drug it always works so much better and we wish we wish we could present that 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 um what what is what is expected compliance well you want to see 80% that's the kind of the benchmark yeah in fact when When you do your per protocol analysis, you say anyone below 80% compliant, we take out of the but they no but the FDA will never accept per protocol analysis.

No. Yeah. Unfort I when I put in this paper I said if we could find a way to to streamline drug development that that's one thing but but AI could help a lot even more. I mean we could say we could do a study instead of being 10,000 it could be 2,000 and it just took the people that took the we could make like you get to your log reduction. Yeah. That's just one example. I mean, um, like I don't know. I don't know how much longer we can keep doing LDL tri I mean, LDL trials with different MOAs.

I mean, and make it we it's it's going to be it's getting harder and harder to do these studies. And so, we're going to have to because of [clears throat] the ubiquity of drugs on the market already and then the amount of LDL lowering that's already in the baseline, right? You know, just you have to be ethical. You can't withhold treatment to patients. So we we we we have uh you know where the we have a a lot of patients that that can access to other drugs and you just you can't you can't deny that to patients in a in a trial.

So it's it's going to be harder and harder to do these studies. So let's come back to statins for a moment. What um 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. And it's I'm sorry, it's not large. It is small, but it's a it's a real and undeniable signal. And and by the way, I would say that it's not just patients going on to get type two diabetes, it's insulin resistance, right?

So p patients who don't progress all the way to type two diabetes, we do see an increase in insulin resistance. What do you think is explaining that? Well, first of all, uh it looks like all LDL lowering drugs, even Pskines have a little bit of a diabetes signal except for obetrop. Yeah. So, so it is about LDL, but that's not entirely true. Don't bile acid sequesterance which lower LDL albeit somewhat weekly show an improvement in glycemic control. Right. Right. I I published a paper on that too.

I mean so um that but that but I'm talking about the mandelian minimization work. We look at you know diabetes and LDL you see a consistent except for the balis sequester part. I'm not sure what the drug matching for a gene would be but it's but not not not that often. You can't the bile sequester gene matching is is not an easy one. But you're right there because because but bile acids are very uh uh energetic. I mean you have to 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. And so you you can see how blocking a bile acid from being reabsorbed, which is why you reabsorb it. So they don't have to worry about making it again can can ultimately uh reduce um potentially sugar blood sugar because it is it is wind binding up energy that you need to replace. So that's that's my simple simple thinking about bile acids. Are are there any patients that are in your clinic that are still on a bile acid sequester?

Yes, there's some. Yes. Right. And what's the these are patients that can't tolerate any other drug hyper cholesterolmia and they we have some. Yeah. And how much LDL lowering do you get with about 10 to 15%. It's not not great. And the side effects? Well, with the GI side effects, there's some that are better. We used we used to use them a lot. We don't use them that much anymore with it once the Zetto came into play because it's pretty much the same as a Zetto, but Zetto is a lot easier to take.

And does a Zetto have an increase in insulin resistance associated with it? You know, not the data would suggest clinically not. But I think genomically there is a slight signal there. But the MPC 10L1, you know, the the knockout types, but um but the uh but certainly PSK9 inhibitors genetically, you know, have that. So what do you think is the mechanism for that? Yeah, I I I honestly don't know. I know I saw this recent data which I think you sh you you talked about where the the change in the in the type of um bile acids that you see um could be a mechanism, but there's been other things too.

I mean the beta cell preservation and so forth. Uh I I don't know I don't it's it's been an enigma about why I don't think anyone knows for sure you know why the but we do know a couple things that I think are help one it is dose related it is age related it's a it's a weight related you know so if you have those you know high dose uh older obese you know more common so if we could say get our our point earlier about not being on high intensity statins why why is it worth the six whatever it is four to % more.

Why not go at a lower dose and lower risk? I think what's more about how do you mitigate the risk and know the MA it is it is a it isn't a we haven't figured it out. I mean this might this might be a reasonable explanation but but up until now there we haven't really figured out why the the glucose issue is a problem. Yeah. Although it again it is important as we noted in our piece that um the asymmetry is still enormous. Right. 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 um 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 um dosing, um I think it becomes less and less of an issue. Yeah. I I that's that's the point. I mean it's the net benefit is still so great. Yeah. So and we unfortunately it's a big discussion with patients very frequently. I don't want diabetes. Why why you giving me this? That kind of thing. So, but your 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. How many other CEP inhibitors are in the pipeline at the moment? To our knowledge, no others. Yeah, we're we're kind of the we're it, you know. So, if we're successful, there'll be a lot there going to be a lot more, but it's very hard to beat obese. It's it's [snorts] got a low dose extremely uh well tolerated in our clinical trials. We saw remind me the molecule that when you guys bought it came from well Amgen through Mitsubishi it's Mitsubi a Japanese company first discovered it then was sold to Amgen and how did what 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 CEP inhibitors and then they sort of abandoned it they wanted they wanted to make a better CTP inhibitor was so one that had you know no fat uptake much lower dose more potency more bioavailable and so they gave We got a great drug.

We got a great drug to work with. And so um uh it's going to be very hard to to match the profile that obetropiv has from a pharmacocinetic perspective. And then to give folks again just the sense of what does it take to develop a drug. So if you look at the money you paid to acquire the drug, what you had to raise to do the clinical trials and what it would take to get to approval, what's the approximate dollar amount to to do that? We've it's well over a billion.

I mean this is but this is not in counting what was cost up until you know we got we got it. I mean yeah it's a billion of of New Amsterdam plus all the money that came before it to get it into phase two. Yeah. So the average drug right now is about three to4 billion dollars to approval. Right. Right. Then that that accounts for the failures too but it might be even more if you count for the failures. But it's it's a lot. It's a it's a lot of money.

We're, like I said, it's a um it's a high-risk Harvey Ward investment. So, we we uh we feel that we uh been able to get to this point and we're we're hoping to have the drug to patients as soon as possible. What do you think overall of the landscape of biotech investing? I mean, we live in this world now where AI is clearly the most interesting and exciting thing to invest in. Capital is flying into AI. it doesn't really matter that you know lots of people are saying hey look this is a bubble we need to you know be a little more cautious with how we do this this feels like 1999 for the internet etc etc um but it's so interesting when you look at biotech companies that it's I mean it's very very difficult to raise money um where do you think we are in the biotech life cycle and why do you think biotech is just forever going to be complicated because of the time horizon The latter is true, of course, but um what's really important is the the macro issues is that we have all these big pharma companies that have you know big sales forces and companies and they have pipelines that are the big big gaps and the cliff the pad cliffs are coming all of them they can't grow you know if in order to grow they have to get new product we have I think in the way the system's set up you know everything ultimately goes generic and So if you see where that is, I mean if if we're talking about if if companies even want to grow 3 or 4% per year, which is pretty minuscule growth, they got they got to add a lot of new products to their pipeline.

And uh and and the way it's worked out is the big companies also have become pretty dysfunctional on innovation about developing new drugs. And it's just that it's just the you know the comp the small companies can be a lot more nimble a lot more flexible a lot more risk take more risk and and don't have to worry about you know corporate you know kind of hierarchy to make a decision so um we we feel that biotech is right now in a in a really good position um and I think AI is going to help a lot on on coming up with the right like I hope you can we can figure out a way to make clinical trials a lot more cost effective and lower cost but even drug discovery we have um uh China for example is um is just become a a huge investment in like for every chemist in the United States there's probably 10,000 in China.

I mean we we have uh they they have the capabilities to really surpass you know anything that we can do from a drug development perspective just by the person power that they have and so that but that sets up an opportunity. I mean we I still think we have the science and the innovation and we have you know the creativity that could lead the world and in coming up with the new ideas but but China is going to going to be able to have us be able to take it to the next level.

um with how to get a drug produced and and then made to to make it to the human data as quickly as possible. Like cloth is a good example. I mean um the hardest part about cloth before we got involved was uh no one could manufacture it. No one could make it effectively. Uh and um then we went to uh China Wooi and they they figured out a process and now it's it's very robust process and it's going very well. also hope to be in in human clinical trials pretty soon.

I mean so so I mean we we we I think we have the uh if you look at it from a global perspective if everyone could work well together you know we have the the makings of a of a biotech revolution but we we got to find the right we have to continue to have a high benefit to to risk kind of ratio too I mean so we have to see how that plays out. Well Michael this is this is really exciting. I love when when we can sort of string together podcasts over a series of years and get kind of an update from um one very exciting idea to another.

I was incredibly excited about Obetropraib when when we spoke about it the first time with John and um everything you've updated us on today only makes that you know just look we just can't wait to get this this this drug um um into the hands of people and hopefully not just for cardiovascular disease but perhaps even more excitingly um for for Alzheimer's disease especially in those E4 patients. Um, so anything else you want to talk about on the cloth front? I know we didn't talk, we didn't spend too much time on it, but um, um, you know, you and I are both involved, which is why I'm a little bit koi to talk about it.

I don't want to I don't like to talk about things that I'm directly involved in as well. Right. Right. I think, uh, it's moving along well. I mean, it's it's um, like I said, the Chinese Chinese the Wooi made it made a make it a great protein. I think the MOA part is still the mechanism of action is still so what we decided you know just to kind of step back um where we were you know year a couple years ago we had this genomic validation that if you have the cloth o gene you're protected against Alzheimer's E4 in particular um we had uh this great animal data consistently showing that if you inject cloth periphilally you improve cognition it went to a primate study and showed great data in the primates got published in nature you know journal uh and so um we we we we believe we had you know a well validated uh target and and and drug but the missing part was the MOA no one knows how it works I mean and then and and turns out I I and by the way that's pretty that's that's a painful point right I mean there's only only about 3% of FDA approved drugs do not have a clear mechanism of action yeah metformin doesn't right Tylenol Yeah, right.

We have other examples of where the MOA is not known. So when you and I, you know, embarked on, okay, how are we going to uh get this to humans? What we had to decide to do was we we basically we have to sort of give up on trying to figure out the MOA. Exactly. because it we just have to find people willing to fund the studies up until human data and and prove that it does improve cognition uh and a human trial. Then I think it's then it's going to be hopefully a solid going forward, not just um hopefully hopefully Alzheimer's as a as a treatment, you know, as a treatment for Alzheimer's uh disease.

Hopefully even a prevention too because it it does have all those criteria. We just don't know the MOA. We do think the um the latest is that the the full length yeah the full length cloth doesn't likely cross the bloodb brain barrier but the there's a there's a um a new fragment that that that may be cleaved that does cross the bloodb brain barrier and that that could be the mechanism of action. We know that peripherally giving it does yep improve um cognition. So we're we're we're very getting closer.

We're getting now the supply is in place and we we're starting the trials to get ready for the uh IND filing that you know the official and we hope to have human data in roughly a year from now. So we can come back and and talk about that with maybe Dena and with together we can talk about the um the um the benefits of cloth. Yeah, it is. It's very high risk, but but it's um you know, it's I I know so many of obviously the investors in in Jocasta and many of them really come at this through the lens of um you know, this is partially a financial investment, but many of them also think of it as philanthropy without the tax break, right?

Which is um uh I'm not just doing this, you know, I'm not just putting my money into this company because I want to make money. I that would be great. But what would be greater is if this drug actually works. Um, 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 um we just we're just watching people suffer so much right now with nothing to offer them. We got to we have to keep working at it.

It's uh yeah, I just lost a a double first cousin. So my uh so my par I had two my mother's brother married my father's sister. So we have all the same grandparents and then she just died at age 72 of Alzheimer's. He was an E4. Yeah. So it's uh so I've seen it. It's it's and I've seen of course a lot of [snorts] patients struggle with it. Uh and uh I wish we had better advice about what to do but we do know I I I do think of course extra.

So one one question we maybe we should end with is what do you do? What what if you're an ApoE4 that like there are some that say but don't even bother checking it because what can you do about it? I think that's the wrong approach. I mean knowing you have it you you can obviously better lifestyle exercise I think that this new taking some DHA if and even though you may not get enough into the brain is still and then keeping your obviously no diabetes normal blood pressure not smoking.

Yeah, there's a lot you can do. I I agree with you. I find it very frustrating when people suggest that. 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. Um, you know, I I think that's I I think I think that's that's probably the wrong side of that bet for me.

But at the same time, you know, Michael, I I do see a lot of people going too far. And I I would almost put myself in that camp of where I was maybe four or five years ago, trying to look too much at at at at biomarkers that that I think in retrospect probably weren't weren't important enough. And and I think that that can, you know, I think when you're looking so hard for things, you start to make signal out of noise. And and I also think that that can create too much anxiety.

And and quite frankly, I I I I I can think of at least two examples where I think 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 uh biomarker. So, um I am just, you know, I'm just I'm pulling for cltho. I'm pulling for obetrop and 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 the the potentially they're working by a different mechanism.

Right. Right. So I love when you can go after complicated diseases from multiple vantage points. And it's clear we're going to need multiple therapies. That's the thing. You're going to need uh obetentropib alone could be a preventive strategy. Uh but I think you might you're going to need more. It's it's going to you're going to need something else as well to uh to make a difference. Well, Michael, thank you for the amazing work you're doing and thanks for taking the time to come out here today.

It was so much fun talking with you. Yeah, so much fun, Peter. Thank you.

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