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

“And with Obicetrapib, he is now at the center of one of the most important open questions in cardiology, whether C-TEP inhibition can finally deliver meaningful reductions in LDL, APOB, LP-little A, and ultimately cardiovascular risk.”

“The history of C-TEP inhibitors, why earlier drugs failed, and what makes Obicetrapib different. Obicetrapib's effect on LDL cholesterol, APOB, LDL particle number, LP-little A, diabetes risk, and cardiovascular outcomes.”

“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 Obicetrapib. That might be the last mechanism. And once that study prevails, the PREVAIL trial, we have a 10th different mechanism of action of LDL lowering and benefit.”

“Let's talk a little bit about Obicetrapib. Your colleague, John Kaserlin, was a guest on this podcast. Gosh, I want to say three, maybe four years ago. Certainly one of the more enjoyable discussions I've had because I tend to really enjoy talking about these things.”

“I think it was eight. Okay. About Obicetrapib. Yeah. It could have been 2006. I feel like it was the fall of 06, but anyway. You're right. It was definitely Christmas, December, got the call somewhere in that range. Yeah. So it's- All right. So first this was Pfizer combining this with Atorvastatin in a clinical trial. Okay.”

“It was stopped for futility when it should have kept going. That was for us a big issue for our drug, Obicetrapib. That was the hardest one to explain. And what were the features of the Lilly drug in terms of HDLC and LDLC kinetics?”

“So, with all of that as background, now let's talk about Obicetrapib, the work that you and John and the team, of course, but let's just talk about how you decided it was worth going after this for a fifth time.”

“And that study is actually coming out this year. It's called the Zeus trial. It's a big, big study coming out. I had sold Corvidia, and John said, let's get Obicetrapib back from Amgen. Amgen had put it on the shelf because Repatha had struggled on its launch.”

“Right. They kept Obie on the shelf for five years? I think they bought it in 2017. They bought it in 2017. Interesting. They actually did a lot of great work on the manufacturing, the process. They worked on it, made it much more cost-effective manufacture, but they didn't do any clinical trials. They just kept it on the shelf.”

“Yeah. Can you remind me and the listeners what that study looked at? So it showed that 45% LDL lowering. Okay. So what was different about OB? It's a much more potent. So it's only, the other CT inhibitors are all in the 100 milligram plus range and they lowered LDL, as I mentioned.”

Our IdentificationSaid as “OB”. We believe this refers to Obicetrapib.

“The reasons to believe, we still have hope that Obicetrapib's HDL-raising benefit can result in a cardiovascular benefit, but we're also focusing primarily on what the other HDL benefits could be, like we're still talking about later, like diabetes prevention and Alzheimer's.”

“Obicetrapib lowered it by an additional 40%. So lowered it from 100 to 60 milligrams per deciliter. Approximately. That was, I think, those approximate numbers. About 40% was the reduction at the end of 12 months versus placebo.”

“It's all over the world, yeah. China, Japan, everywhere. It's 400-plus sites. And it's a global study. And the outcome of that study, should it be positive, would be approval in Europe and North America for Obicetrapib in secondary prevention? We actually don't need it for approval in Europe.”

“And we hope Obicetrapib can be part of that treatment paradigm. From a purely cardiovascular standpoint, how do you see Obicetrapib being used? Should the outcome trial end in the fashion that you would expect.”

“It lowers mostly the non-small particles. What does Obicetrapib do well? It lowers the risk of diabetes based on our Broadway trial data, as well as other CTV inhibitors. It lowers LPLA in that 50% range in that moderate band.”

“It lowers LPLA in that 50% range in that moderate band. And it lowers the risk of diabetes, lowers LPLA, and lowers the small particles by 90%. And so it would be a great companion drug to statins.”

“And if you need even more potent, you can add the azetamib combo pill. So we believe that with OB alone and OB with azetamide, 90% of patients are done with their lipid treatment. And so that's how we think for primary care doctors, that's what they're looking for.”

“So that's the background about APOE4, and it's a lipid gene. And what is important about Obicetrapib is that we had that genomic data, we had the animal data, and then we know that HDL is the one lipoprotein that does interface with the brain.”

“the biomarkers improved. 181, amyloid 4240, GFAP, neurofilament light, all got better with Obicetrapib. And that's what we published in our paper. So we felt that this data really confirmed that Obicetrapib was in fact active in potentially preventing Alzheimer's disease.”

“And so they gave us, we got a great drug. We got a great drug to work with. It's going to be very hard to match the profile that obicetrapib has from a pharmacokinetic perspective. And to give folks, again, just a sense of what does it take to develop a drug. So if you look at the money you paid to acquire the drug, what you had to raise through the clinical trials,”

“I was incredibly excited about Obicetrapib when we spoke about it the first time with John. And everything you've updated us on today only makes that, look, we just can't wait to get this drug into the hands of people.”

“So I'm pulling for Clotho, I'm pulling for Obicetrapib. And then, of course, if they're successful, what that's going to do is open up the door for more things. But what I love about the two of them is potentially they're working by a different mechanism.”

“And it's clear we're going to need multiple therapies. That's the thing. Obicetrapib alone could be a preventive strategy. You're going to need more. I need something else as well to make a difference. Well, Michael, thank you for the amazing work you're doing. And thanks for taking the time to come out here today.”

“we talk about from time to time, but I have a feeling you're going to add a lot of value to my somewhat limited knowledge, which is the most up-to-date thinking on the role of fish oils, DHA and EPA. But you want to talk about it through cardiovascular disease first or talk about it through Alzheimer's or both?”

“disease called Epanova. We went to an outcome study and it didn't work, but it was DHA and EPA, but mostly EPA had some DHA. And that was four grams?”

“What that says is that EPA does work on reducing events. But not through triglyceridal. It's not for triglyceride lowering. It's more for the antithrombotic, anti-inflammatory effect, which brings me to DHA. So DHA, I still think has a lot of health values that we should talk about, especially for the brain, because the brain is predominantly DHA.”

“brain is predominantly DHA. That's the fatty acid in the brain. Now, the problem is with DHA, we tried DHA supplementations on cognition, didn't really show much. You've had Hussein Yassine here, and he's talked a lot about, but ABOA4 people, one of the other things is they don't get as much DHA to the brain.”

“membrane concentration of EPA and DHA, and it's very low, 4%, and they were to supplement with a very high-quality over-the-counter EPA and DHA, and they were to get that to 10%.”

“inability to get the DHA in the brain? You have to get the lyso-PC form to get to the brain. You have very limited capacity to convert that into the lyso-PC form. Yeah, absent another. Yeah. So you have to make this lyso-PC form, which you can do with either a fish-based oil or a krill-based oil.”

“You can make lyso-PC DHA. So that's the next hopeful excitement around the DHA and brain health that I think needs to be further. But there is no version of that on the market today.”

“I think that's the wrong approach. I mean, knowing you have it, you can obviously have a better lifestyle, exercise, taking some DHA, even though you may not get enough into the brain is still, and then keeping your, obviously, no diabetes.”

“So I got very interested in lipids in medical school. So I did the original niacin trials that went back into the 80s, late 70s, actually. And then after training residency, I started doing research in my fellowship on omega-3 fatty acids for the lipid effects.”

“They both were equally bad. So I then went on to start medical school. I took niacin in med school. As soon as statins became available, I started taking a statin. My brother, who's also a family doctor, went on and become a vegetarian, really strict diet, did not take statins until much later.”

“How significant relative to the breast is the same. It was modest. That was modest. Not nearly the same as statins. Obviously, niacin has a lot of side effects. I took niacin as before statins because that's what we had. You get flushing and GI side effects and liver issues and stuff like that. But no, we had niacin.”

“It was two studies, AIMHI and HPS Thrive trial. Both showed niacin on topostatins did not lower LDL, so did not lower events. The Thrive HPS2 trial there was, it looked like if you looked at it in another way to look at the analysis, it did lower events by LDL lowering it because it lowers LDL also.”

“And then after training residency, I started doing research in my fellowship on omega-3 fatty acids for the lipid effects. I was the first one to use fish oil capsules to treat lipid disorders.”

“How much? Four grams, yeah. It was called the strength trial. I think what I learned, because I've always been a big advocate for omega-3s for triglycerid lowering, and there's really two reasons why omega-3s can reduce risk. One is triglycerid lowering, and the other is by antithrombotic effects.”

“And so there was really two reasons to think why omega-3s could lower risk. And one was through the EPA antithrombotic effect. The other is triglyceride lowering. And so what strength was set up to do was really a triglyceride lowering trial, and it didn't work overall.”

“Completely independent of the cloth at work. Right, exactly, yeah. That's coming. And I've been on omega-3. One of the things that really, until this receptor was identified, we couldn't understand why DHA doesn't get into the blood-brain barrier like you think. Most of your DHA has to come from the blood.”

“it's- All right. So first this was Pfizer combining this with Atorvastatin in a clinical trial. Okay. Go back from that a decade into the discovery of yet another mechanism, because you've already alluded to this, which is lowering LDL is the goal, but there are many paths to get there.”

“Again, all on maximal statins, majority on high-intensity statins, like 70% were on 20 or 40 of Rosuvastatin or 40 or 80 of Atorvastatin. They're all very well treated. And we got roughly around a 35% LDL-lowering benefit. And then adjusting for placebo, a little less than that. But it was around that percent change at 12 weeks and then it continued for 52 weeks.”

“I don't like 80 milligrams of Atorvastatin in particular. I don't like 40 milligrams of Rosuvastatin. Have you seen Tom Dayspring put out a beautiful figure? It's one of your classic Tom figures that he pulled out of all the literature, and it shows the dose response of every statin.”

“disease called Epanova. We went to an outcome study and it didn't work, but it was DHA and EPA, but mostly EPA had some DHA. And that was four grams?”

“It was 50-50 primary. And so if I had to do it all over again, I would have made it all secondary, just like mostly the REDUCEIT trial was, which is the EPA-only trial. So the Reduced trial showed a benefit, and it could have been likely had some effects of the mineral oil placebo, tilting it a little bit.”

“membrane concentration of EPA and DHA, and it's very low, 4%, and they were to supplement with a very high-quality over-the-counter EPA and DHA, and they were to get that to 10%.”

“I was the first one to use fish oil capsules to treat lipid disorders. And then from there, I got involved with all the statin trials. It's been my passion is to be involved in clinical trials. And I still a cardiologist, did the usual stuff that cardiologists do, and then focused primarily on prevention.”

“we talk about from time to time, but I have a feeling you're going to add a lot of value to my somewhat limited knowledge, which is the most up-to-date thinking on the role of fish oils, DHA and EPA. But you want to talk about it through cardiovascular disease first or talk about it through Alzheimer's or both?”

“You have very limited capacity to convert that into the lyso-PC form. Yeah, absent another. Yeah. So you have to make this lyso-PC form, which you can do with either a fish-based oil or a krill-based oil. You can make lyso-PC DHA. So that's the next hopeful excitement around the DHA and brain health that I think needs to be further.”

“Don't you think it'll just be used off-label for that reason anyway? Well, we can unfortunately. You have nothing to do with that, but I'm just saying, like, look, people were using PCSK9 inhibitors off-label for LP-little A reduction the moment it became clear that it was lowering L P little A 20 to 30 percent.”

“Patients who don't progress all the way to type 2 diabetes, we do see an increase in insulin resistance. What do you think is explaining that? Well, first of all, it looks like all LDL-lowering drugs, even PCSK9s, have a little bit of a diabetes signal, except for Obicetrapib. It's just the opposite. Yeah. It is about LDL.”

“But certainly PCSK9 inhibitors genetically have that. So what do you think is the mechanism for that? I honestly don't know. I saw this recent data, which I think you talked about, where the change in the type of bile acids that you see could be a mechanism.”

“events by LDL lowering because it lowers LDL also. That was actually post-tricetrapib. So tricetrapib was the Pfizer CTP inhibitor. Everyone was rushing to get a CTP inhibitor because it raised HDL 50%, 75%. We thought we'd have the cure for heart disease. Every 1% increase in HDL in these other trials lowered risk by 3%.”

“Okay. So then the Roche compound comes along. What was the story with that trial? So it's a weak CTP inhibitor, and they even call it a CTP modulator, a very safe drug. And it raised HDL 30%, maybe 40% in some trials. So not much weaker HDL raising effect, no LDL effect.”

“It's not clinically significant. But that means you're going to be tolerating patients on Crestor and Zetia walking around with AST and ALT of 80. Right, right. And the reality of it is, I just have a hard time believing that that makes sense.”

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

“And so the similar would have happened, we believe, with evacetrapib in the Accelerate trial. Although with Repatha and Pralulin, we did see benefit at about two years. This was only a 15% LDL lowering. Yeah, yeah, yeah, yeah, yeah. So it's also interesting in the Odyssey outcome study, which is the Pralulin, which is the other PCSCAT inhibitor, if you look”

“Amgen had put it on the shelf because Repatha had struggled on its launch. They deprioritized it. So they kind of had it sitting there ready to go into phase two, maybe even right into phase three potentially.”

“people to take off-target use. There are plenty of people using GLP-1 agonists today for neuroprotection, even though that would still be considered sort of off-label as well. Yeah. Unfortunately, I can't talk about that as a CEO of a biotech company about off-label use.”

“You have very limited capacity to convert that into the lyso-PC form. Yeah, absent another. Yeah. So you have to make this lyso-PC form, which you can do with either a fish-based oil or a krill-based oil. You can make lyso-PC DHA. So that's the next hopeful excitement around the DHA and brain health that I think needs to be further.”

“That's only about 3% of FDA-approved drugs do not have a clear mechanism of action. Yeah, metformin doesn't, is it? Right. Tylenol. Right. We have other examples of where the MOA is not known. So when you and I embarked on, okay, how are we going to get this to humans?”

“I don't like 80 milligrams of Atorvastatin in particular. I don't like 40 milligrams of Rosuvastatin. Have you seen Tom Dayspring put out a beautiful figure? It's one of your classic Tom figures that he pulled out of all the literature, and it shows the dose response of every statin.”

“Yeah, metformin doesn't, is it? Right. Tylenol. Right. We have other examples of where the MOA is not known. So when you and I embarked on, okay, how are we going to get this to humans? What we had to decide to do was we basically have to kind of give up on trying to figure out the”