Activity Transcript

Roxana Mehran, MD:

Hello, I'm Roxana Mehran, professor of medicine and director of Interventional Cardiovascular Research in Clinical Trials at the Icahn School of Medicine at Mount Sinai.

Christie M. Ballantyne, MD:

And I'm Christie Ballantyne, professor of medicine, chief of the Section of Cardiovascular Research, and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Texas.

Dr Mehran:

Dr Ballantyne and I'd like to welcome you to this program, "Back to the Future: Revitalizing the Role of Cholesteryl Ester Transfer Protein Inhibition, or CETP Inhibition, in Cardiovascular Risk Reduction." And you might say, "Well, why are we talking about CETP inhibitors at this stage?" There are so many great therapies, and we're going to talk about all of those. But most importantly . . . and I think what I'd like Dr Ballantyne to continue to talk about, is this residual risk that we are all seeing.

We know that especially after a coronary event, like acute coronary syndrome (ACS), there are a lot of events that happen, especially early on, and the risk continues to stay basically the same in those patients. They continue to have recurrent events.

And we're also seeing that, not just postevents, but we're seeing a lot of residual events even in our patients with high atherosclerotic burden. And I think very importantly is this whole new idea of hypothesis shift. The idea of maybe thinking about raising high-density lipoprotein on top of lowering low-density lipoprotein. Christie, why do we need to go further?

Dr Ballantyne:

Well, it's been a really interesting journey. I got into this field a long time ago, beginning of my career, in terms of the concept of how do we reduce atherosclerotic cardiovascular disease [in] advance? I thought if we did that, we'd solve everything. It turns out heart failures may be a little more complicated, but atherosclerosis is the major thing that we're focusing on, particularly in younger people.

So, it was LDL and HDL, along with our traditional risk factors, hypertension, smoking. And we thought if we could raise HDL, based upon the epidemiology, then we're focusing on HDL cholesterol, that we would reduce events. I think sometimes epidemiology, Roxana . . . something like the oral estrogen story. The observational data suggested that people had fewer events . . . and so we did the trials and it didn't work. It turns out to be more complicated. Sometimes with observational studies, you have other confounders.

So this has been the case, is that we really thought we had the statins for LDL (reduction), and we thought, "Okay, if we have the agent that will raise HDL cholesterol, we'll basically solve the story." And it's turned out to be substantially more complicated. Now, 1 important thing is that we do know is that the data have been very powerful about LDL, and also let's broaden that to the ApoB-containing lipoprotein. So you've got LDL, which for most people is the major ApoB lipoprotein. But also for other people, if you see a high triglycerides, they've got the very low-density lipoprotein (VLDL) remnants and intermediate density lipoprotein (IDL) particles, and now a lot more focused on lipoprotein A [Lp(a)].

So all of those particles contain ApoB, they go in the arterial wall, they get trapped in there, and we have the atheromatous plaque development, and if you wait too long and don't do anything . . . Roxana, you end up seeing them in the catheterization (cath) lab, because they end up having either structured lesion, or worse, they have an ACS with plaque rupture, thrombosis.

So, great progress on LDL and ApoB particles. What about on the HDL side of things? Now that's a lot more complicated. Now, it has also been obviously, in terms of our concept of residual risk, that we use the statin. We've lowered LDL, a moderate amount, very successfully. You still have to focus on hypertension, hemoglobin A1c, obesity, inflammation. And we mentioned Lp(a), and statins don't really touch Lp(a). In fact, they actually slightly increased Lp(a). So this was something that made us think, "Well, if we could get the LDL down, and raise the HDL cholesterol, then we would really have the problem solved." It's turned out to be a lot more complicated.

And in regards to CETP, this goes back to torcetrapib. You know, Roxana, you and I are both familiar, there were a lot of outcome trials that were done with these agents, and the results were surprising . . . and maybe a little bit confusing, in regards to certainly on the HDL cholesterol side of things.

Dr Mehran:

It's not so straightforward. And I think that's what you really are telling us. And I think certainly the issue is that several trials that have been done in the past, got terminated early for futility.

And then it really wasn't until we had the REVEAL trial with anacetrapib where we saw this major adverse cardiovascular events (MACE) reduction of 9%, 20% in 2.3 years follow-up, pretty good results. This was REVEAL, a really nicely conducted trial. The long-term efficacy, with intensive statin therapy, for reduction of the first major coronary events was pretty impressive. In fact, it looked as if you compared it to the reduction in statin trials; it plotted very similar to that size of absolute reduction in non-HDL cholesterols.

But since then, we've had a lot of great therapies.

I think the clinician is sort of like, "What are we supposed to do? We've had statins, fibrates, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, now, bempedoic acid, inclisiran, with a small interfering RNA (siRNA). And I think IMPROVE-IT showed the addition of ezetimibe being that much more effective, on top of simvastatin. And then of course we have data from the FOURIER and ODYSSEY trials, those are, I think, the most impressive reductions. Albeit in patients with, they're not really primary prevention. These are high-risk patients with cardiovascular risk and prior ACS.

And I think very, very important evaluation of the potency of, and how much of the potency of the reduction of LDL cholesterol has to do with reducing these important major adverse cardiovascular events.

And then in the statin-intolerant patients, we just most recently came through the CLEAR OUTCOME study with bempedoic acid. A modest outcome, but not bad, significant reduction in statin-intolerant patients.

I think for me, one of the most exciting things that I saw is seeing visually what was going on as you were reducing LDL cholesterol with a high-potency PCSK9 inhibitors, in PACMAN-AMI and HUYGEN studies, where they showed the thickening of the fibrous cap, and the lowering of the lipid content of the plaque, which I think was also incredibly interesting.

And as we're going to the newer guidelines, we're even asking for lower LDL, and coming back to you, Christie, how are we doing with this? Are we actually achieving these goals, and do we need something more, given some of the studies that are going on now, and the ones that we're planning hopefully on CETP inhibitors?

Dr Ballantyne:

So, I do think it's really important to tie together the concept, look at event reduction, and also what's happening in the coronary artery. And that's a little bit, sometimes cardiology's a little bit focused on the heart. Maybe ignore cerebral vascular disease, and peripheral lower extremity arterial disease, which are very important also. But clearly, the early trials were with coronary angiography, and people were disappointed that you didn't see these gigantic chains, but it was pretty clear that you saw a stabilization. I go back to these, we were involved with one called the LCAT study, but if you looked at those trials, it looked like you needed to get really LDLs down to probably well below 100 mg/dL, which early in the days you thought, "Well, that's so aggressive." Before you really had on average any, a lot [of] regression. And that came back in some of these very-high-intensity statin trials, showed some modest regression.

And that was looking at the lumen, and you have the PRECISE-IVUS trials also showing the benefit, and now with some with the newer technologies, looking at changes in plaque composition, plaque thickness, so it's pretty exciting that, in fact, the data are fitting that really you need to drive LDLs very low to get the process to be quiescent, and in fact, to a certain extent, heal the artery.

You get rid of that atheromatous plaque, you get a more stable, thicker, fibrous cap. So, I think the imaging further supports we had . . . based upon animal studies, and other smaller things, that you really want to get well below 70 mg/dL. And what we're seeing in these trials is when these guidelines have been shifting. . . . So the Europeans first came out with LDL-C less than 55 mg/dL, and the targets have been moving with it, for the American College of Cardiology (ACC) expert consensus pathway came more recently also saying, "In our very-high-risk patients, try to get to less than 55 mg/dL."

The data have shown, you've mentioned the data out of 48 ODYSSEY outcomes, those patients were on average around 30 mg/dL, and there was no safety issue with it, and there were better outcomes. And the European Society of Cardiology (ESC) guidelines talked about you see these people that. . . your frequent flyers, they're coming back with recurrent events, trying to get to less than 40 mg/dL in those individuals.

Now, it's great that we have these guidelines, but if we go and look for the GOULD registry in the United States, and we really haven't done very well. In the GOULD registry, most everybody was thinking even before this 55 mg/dL came out with the Europeans, a lot of the cardiologists were thinking this is a good number, but very few patients were less than 70 mg/dL, much less 50 mg/dL. And there was very little utilization of combination therapy, which is interesting. The same clinicians who had about 8% of the people on combination therapy (for lipid lowering) had 70% of the people on combination therapy for hypertension.

So, we've seen over time, part of it is that why are we doing so poorly, is that the guidelines have changed. Some of this is also, is that there's pushback from patients, we've all seen this. People know that the highest dose of a medication does have more side effects. Myalgia is a very common complaint. It's been an issue where there's been some difficulty in getting people on the highest dose of statin, and there's very little utilization of combination therapy. You mentioned ezetimibe, it's an inexpensive generic medication, not terribly potent. Bempedoic acid is also, it can be added on a statin, it's more effective than people not on a statin, because it's in the same pathway with cholesterol synthesis.

So, we have this issue that we haven't done a great job getting people to our targets. And a lot of this is because of the lack of utilization of combination therapy, and hypertension, we know you have to use combination therapy. To treat diabetes, everybody gets it. You're going to probably be doing combination therapy. So, we have this. Now the other problem that has come up in regards to cholesterol medications is the issue of access, jumping through the hoops to get a drug approved and reimbursement. So, it's an additional problem here.

So, we do have a lot of residual risks. Statins are fantastic agents. They've made a tremendous benefit, but we know that overall we're still also not doing a great job in terms of lifestyle, diabetes, blood pressure. And we've got some major gaps in regards to LDL.

Dr Mehran:

Now, there's no question that it's been a challenge. I can tell you in my own practice how challenging it is to really get to the goal of where you need to be without the side effects, without issues with payers, etc. But there's now really this whole program is about cholesteryl ester transfer protein inhibitors. And there's this interest there now. And I really wanted you to dig in and tell us why this new interest, why are we now. . . . Are we back to the future? Or what data are there? And maybe you could tell us a little bit about some of the early data that is keeping you excited, and then why we are thinking about a major outcome study.

Dr Ballantyne:

Well, when we look at CETP, it's important to look at the genetics. Initially, we looked at some of these cases, for example, in Japan where you had CETP deficiency, very high levels of HDL cholesterol. You focus on HDL cholesterol. But it's important, cholesteryl ester transfer protein, you have an exchange of cholesterol between LDL and HDL particles. It's making an impact on both particles and also triglyceride particles, cholesterol. It's exchanged between all these particles.

So what ends up happening is, when you're doing this, when you're taking some of the LDL cholesterol and putting that into an HDL particle, then basically you're delivering less cholesterol to the liver from LDL. That increases the LDL receptors. So you end up having a reduction in LDL cholesterol.

Now what's been done, and if we think about that, it's a different mechanism. But if we look at how statins work, statins inhibit cholesterol synthesis, they increase alveolar receptor expression. That's the same thing you think ezetimibe does, as less cholesterol delivered to the liver increase alveolar receptor expression. Bempedoic acid blocks cholesterol synthesis also. So this pathway, in removing more LDL, and therefore reducing LDL cholesterol and also ApoB particles. That's a mechanism that's been really kind of common to the other agents which we have been studying. You're improving the clearance of LDL and ApoB particles through the liver, different way of doing it with a CETP inhibitor.

Now, why is that important? It's important because if we go back and then do re-look at the genetics, instead of focusing on the HDL cholesterol changes, we look at the genetic variants in CETP. They were associated with reduction in ApoB. The LDL and ApoB particles, which we know are the atherogenic particles.

We see a very interesting story, and this was some elegant work by Brian A. Ference, MD, MPhil, MSc. He showed us a CETP gene looking at a bunch of snips of your gene score. For the amount of ApoB reduction, he saw the same kind of CV event reduction that you would see with the genetic pairings in PCSK9 and 3 hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase and Niemann-Pick C1-Like 1 intracellular cholesterol transporter 1 (NPCL1L1), that is the target of ezetimibe.

So it's a very similar situation. That's exactly, Roxana, and you showed it earlier, the REVEAL study showed that for the amount of reduction in LDL, non-HDL cholesterol, you've got the same event reduction as you did with a statin. So it's a different focus here than we had in the past. Not just looking really at the HDL cholesterol, but looking at the reduction in ApoB, LDL continued lipoproteins.

So, this, I think, is the interest.

Dr Mehran: Yeah, no question.

Dr Ballantyne:

Those molecules have been different, and obicetrapib has been looked at, and we have the ROSE study, a phase 2 trial, looking at a 10-mg dose of obicetrapib, compared with placebo. These were people on high-intensity statins, so that's the scenario that we're facing in practice. Can we get a further reduction? And the answer was a very resounding yes, you can. It was a 51% reduction when you added 10 mg on top of statin therapy.

And that's by the ultracentrifugation methodology, which is not used in clinical practice, but by Friedewald, which is 46%. So very good reduction in LDL cholesterol, reduction in ApoB of 30%. Now these are larger than what we're seeing in the anacetrapib trial, so substantially more LDL reduction, non-HDL reduction, down by 44%. You showed the data with bempedoic acid, that was about a 18% LDL incremental reduction in that study. So, we're talking some major LDL reductions. HDL went up, and that had been shown with the other agents. Apo(a) went up, but they had not shown these kinds of LDL reductions. And very interestingly, there was a reduction in Lp(a), and it wasn't focused on patients with high Lp(a). It was very encouraging, because, as I mentioned, statins don't lower Lp(a), and often we're left with a high residual Lp(a).

So really some exciting data out of the ROSE study. I recently had the chance to work with the group in terms of first author of the ROSE 2 trial. Obicetrapib is a mechanism of action with CETP inhibition, what about if you add it to ezetimibe? That would be another option for people who were having trouble with statins. This was a phase II study comparing the obicetrapib 10 mg, obicetrapib 10 mg plus ezetimibe, vs placebo. And in fact, 10 mg obicetrapib plus ezetimibe vs placebo reduced LDL 63%. So, that's very potent in terms of the ability of a single-pill nonstatin to give a lot of LDL reduction.

Well, those are the phase 2 data. I think the excitement has been building, because their phase 3 program is really rolling right now. And what you've got is the BROOKLYN study, looking at a very important population that's familial hypercholesterolemia, and it's the 10-mg dose [of] obicetrapib compared to placebo. People who are on statin therapy. That's about 300 patients. Or larger, broader study is called BROADWAY, 2400 people. This is going to be, once again, 10 mg obicetrapib vs placebo, 2-to-1 randomization for this.

There's also a phase 3 combination study beginning, looking at ezetimibe, with obicetrapib vs placebo. But to me, most exciting, Roxana, and I know you've been very involved, the PREVAIL study.

Dr Mehran:

What I love about this program is the judicious way of going about and studying, as you just described so beautifully, all of the steps of all the clinical trials that have been done for this particular compound.

And now after ROSE and ROSE 2, as well as BROOKLYN and BROADWAY, we're really on for the show. And that would be PREVAIL, which is the CV outcomes trial. Really designed, and powered, for morbidity and mortality in patients with established ASCVD. And these patients would be on maximally tolerated lipid-lowering therapy, including high-intensity statins. And it's those same patients that we talked about, you can't get them to the guideline-directed goals. They're at high risk for events, and they have an unmet need for something more.

And so, what we're doing is hopefully around 9000 patients are going to be randomized in a double-blind placebo-controlled fashion, on top of their maximally tolerated statin, is obicetrapib 10 mg vs placebo. And we're going to look at these patients at 1, 3, 6, and 12 months, and it's a 4-point MACE of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, and nonelective, urgent need for a coronary revascularization.

And, of course, looking at their LDL, and new-onset diabetes, which I think is very, very interesting for all of these compounds, because overall we are seeing a trend towards reduction of new-onset diabetes. So, we would really be powered, for the very first time, with 9000-plus patients to look at the hard outcomes and some of these really, really important secondary objectives that are getting these patient's LDL to goal, and of course, averting new-onset diabetes. I'm really excited about this.

Dr Ballantyne:

One thing I like is it's including high-risk primary prevention.

Dr Mehran:

Yeah.

Dr Ballantyne:

Because we know it's a continuum, that when you have people who are high risk, one day, they're high-risk prevention. The next day, they're ACS or they've got a revascularization or something else. So it broadens it, because you mentioned those PCSK9 trials were only secondary prevention, and we like to be able to have agents that look to be this effective, available for high-risk primary prevention. So I think that's a really nice plus part of the trial design, when the duration should be sufficient. The PCSK9 trials got stopped a little early. They were shorter than optimal to show the benefits. But the nice thing also is, like you said, we do know statins are fantastic agents. But high-intensity statin, slight increase in diabetes. So if you could add something that gives a slight decrease in diabetes, that would be a nice plus to show on it.

Dr Mehran:

I'm hoping it will get even longer beyond a year follow-up on patients like this. Because we know that a lot of these events accumulate over time, and the reduction of events are just going to be, I could just see these curves separating even on top of the high intensity.

Dr Ballantyne:

Yeah, I think that's the thing is, doing an outcomes trial that's long enough duration to really capture the benefit is very important with it. So it's nice to see that it's well thought out. You've got the lipid program and you've got the outcomes trial, and it's an interesting molecule. So it would be great, I know it's for the clinicians and for those if you're treating patients, hopefully it would also end up being . . . I know that they have advocated that they would try to make a drug that's going to be accessible, which would mean coming out with a pricing strategy that would make it accessible. It has been frustrating to not be able to give to our patients. We've had some really great therapies, but they're hard to get for people (to obtain) and particularly high-risk primary prevention, because we don't have the outcomes trials with that. So the insurance companies have gone without it.

Dr Mehran:

No, it's really an exciting area. Today we really had a fantastic opportunity to talk about CV risk reduction, did we not? I mean, and a lot about the hypothesis of lowering LDL, raising HDL. The multipronged approach, really going over the cholesteryl ester transfer protein inhibition, and that biology and why we're turning our attention to that.

I think today, with our fantastic expert, Christie Ballantyne, and his beautiful rendition of what's going on and how we should be looking at the future in a multipronged approach. It's really been fantastic.

I really want to thank you certainly, Christie, for joining me in this discussion. Thank you all, our audience, for participating in this activity. Please continue on to answer the questions that follow this and complete the evaluation. Thank you for participating.

Dr Ballantyne:

Thank you.

This transcript has not been copyedited.