Today I'm going to talk about addressing the unmet needs in LDL cholesterol lowering. What can we expect? My name is John Kastelein, and I'll be delivering this lecture with great enthusiasm. These are my conflicts of interest, and this is the legal disclaimer that is always needed for such a presentation.

Now, if you look in the blue square, the two main issues we have in cardiovascular disease prevention are the fact that it's not only the absolute reduction of LDL cholesterol but also the duration of that reduction that is the key to reducing cardiovascular risks. It has taken us,

since the introduction of the statins in 1988, 1987, until now, to understand that these two premises are all important in CV risk prevention.

If we do understand this, then the next question is, how well are we treating our patients with ASCVD? Are we treating them with large absolute LDL reductions and are we treating them long enough, meaning we start early enough? In fact, we are not.

The DA VINCI study led by Professor Kausik Ray has shown that in order to get to the 2019 LDL goal from the European ESC/EAS guidelines, only 33% of patients, and this actually is mirrored by studies from the United States, and we now know that between 2/3 and 3/4 of patients with ASCVD actually reach their goals.

What would be the way to improve this? Fortunately, we now have the first trial with outcomes to show that if you compare high-intensity statin alone versus moderate-intensity statin with ezetimibe, that, in fact, in terms of MACE outcomes, after three years there's no difference. Meaning the combination therapy is non-inferior to the monotherapy. It also means, undoubtedly, that the adherence to the double regimen is better, but also, as a last point, that the mode of action to lower LDL has no impact on its ability to reduce MACE. Those are three very important takeaway messages that we get from this trial.

This editorial that Professor Ray and myself wrote in European Heart Journal recently provides a scheme whereby patients with very high CVD risk and extremely high CVD risk actually could start with combination therapy right away. Not first push the dose of a statin to its highest dose and then wait till that's not enough, or the patient cannot tolerate it, and then only add a second or a third thing. No. Actually, in those patients, start straight away with combination therapy. I am convinced that this is the way of the future.

How can we improve in practice? In fact, we have a number of drugs that we can add to statin therapy. The first was ezetimibe. You've seen that in the previous trial. The second is bempedoic acid, and you can see here that bempedoic acid monotherapy added to high-potency statins, delivers an extra kick of about 16% to 15%.

But the true power of bempedoic acid lies in its combination with ezetimibe. Since these two mechanisms are complementary as you can see in this scheme, what you end up with is the shaded bar. In blue, ezetimibe monotherapy, in green bempedoic acid monotherapy, and in the shaded bar, the combination. You can see that that combination really packs a punch. It's 36%, so when you add that to a statin therapy, you have an additional 1/3 of your LDL level at that time. That, of course, is clinically very significant.

Then there's another mechanism that is a recent kid on the block, that's ANGPTL3 inhibition. It's the only mechanism that is capable of lowering LDL without having to upregulate the LDL receptor. In that sense, it's a unique mechanism. What it does, if you inhibit ANGPTL3, you dis-inhibit lipoprotein lipase, goes up, you dis-inhibit endothelial lipase, goes up. You change the remnant particles in such a way that they're avidly taken up by the liver, so they cannot become LDL. Actually, they're already cleared away. That's a novel and very interesting mechanism.

You can see here, this is the practice, evinacumab is a monoclonal antibody against ANGPTL3 given to homozygous FH, and you can see an almost 50% lowering of LDL in these very hard-to-treat patients. Because this therapy does not need the LDL receptor, you can actually see that patients who have no LDL receptor at all, null/null in red here, actually have the same response to ANGPTL3 inhibition, than patients who still have some residual activity. That is wonderful news because, normally, there is very little that can help these null/null patients.

Slowly, there's a new treatment algorithm emerging for homozygous FH. Start with a high-intensity statin, then you add ezetimibe, then you add evolocumab, and last, you add evinacumab, the monoclonal antibody against ANGPTL3. That quadruple therapy is capable of getting a large proportion of homozygous FH patients to very reasonable LDL cholesterol levels.

Then there is, since shortly a third possibility, and actually, it's a fourth because I have not addressed PCSK9 in this lecture because that is adequately addressed by many other people. There's ezetimibe, PCSK9, ANGPTL3, and now last, there is CETP.

How does CETP inhibition fit in this pathobiology? Initially, it was thought that because high HDL is associated with a low incidence and prevalence of coronary disease, that CETP inhibitors would reduce heart attacks and strokes because they increase HDL. Actually, we now know that that's not true.

This is a trial published in The New England Journal with a drug called dalcetrapib the CETP inhibitor. That trial was large, recent MI patients, 16,000, were randomized to placebo or this early CETP inhibitor.

If you look at the changes in lipids, you can see that there was a 40% increase in the upper panel of HDL, but there was no effect on LDL whatsoever. As you can see, in the Kaplan-Meier curves on the right, there's absolutely no benefit in terms of the MACE reduction from this drug. Very interesting, this drug was the final nail in the coffin of the HDL hypothesis because if you raise HDL by 40% with a drug, but there's no effect on MACE, it must mean that raising HDL does not help. We now understand that much better. Raising HDL is not going to reduce MACE. Dalcetrapib did not move LDL, and therefore, did not move MACE.

The next trial was evacetrapib. Another large trial, 12,000 patients with recent acute coronary syndromes.

That drug was actually tested in this trial by a direct assay for LDL cholesterol, and the company and everyone else thought that this drug lowered LDL by 31%. Now, if you go down 4 lines, you see the apolipoprotein B reduction, 15.5% from baseline. Now, if you lower apoB by 15.5%, you must lower LDL by about 17%. 31% is simply not possible, so that is actually the wrong assay. When you overestimate your LDL lowering, you're going to underestimate the number of patients you need and the duration. Remember what I said in the beginning, absolute LDL difference times the duration of exposure.

I have put three Kaplan-Meier curves on this slide for you. The top is the IMPROVE-IT trial, simvastatin versus simvastatin plus ezetimibe. In the middle is placebo against evacetrapib, and in the bottom, is placebo against anacetrapib, the Merck CETP inhibitor. These drugs are very similar in their potential to lower apoB. In fact, in these three trials, the absolute apoB reduction was basically similar. If you then look at when the Kaplan-Meier curves diverged, you see they do so at about 30 months. That was exactly when evacetrapib was stopped. That trial with a reasonable drug actually was stopped too early so that CVOT was underpowered and too short.

Then, fortunately, Merck did a trial that was even double the size of the other trials, 30,000 patients. Anacetrapib. Very interesting is that that trial actually reported after 4 years, a 9% benefit. Some people thought that that was a disappointment, but no one realized that the baseline LDL in that trial was only 60 milligram, and a drug like evacetrapib only lowered LDL by 17%. If you multiply the 60 by 17, you end up with an absolute LDL difference of 11 milligram per deciliter. That's tiny, and that predicts exactly the 9% benefit. That trial fit on the CTT meta-regression line, and it validated CETP inhibition as a principle.

What were we looking for? We were looking for a CETP inhibitor that didn't have the side effects, had a normal half-life, and did lower LDL robustly because we now understand that in order to work, the CETP inhibitor must lower LDL.

The ROSE trial, we tested this drug, obicetrapib, 5 and 10 milligrams versus placebo. As you can see here, the 10-milligram dose lowered LDL, measured by the gold standard, ultracentrifugation by 51%.

Here you see the waterfall plots, and actually, in the 10-milligram arm, a more than 60% reduction was observed in about 40% of patients, so this is a very powerful LDL-lowering drug.

What about the safety? The safety of this drug, and we've seen seven phase I trials and three phase II trials is very good. There are no serious side effects, both in the 5 or 10 arm. There were no reasons for discontinuation of the study drug. So far, as you can conclude from the phase I and phase II, the safety of this drug really looks well.

How are we going to make sure that we don't have the same disappointments as in the past? Look at the blue diagram. Our outcome study is called PREVAIL. We have started this outcome trial in Canada, the United States, China, Japan and Europe, and the Middle East. The baseline LDL will be 100. Our LDL lowering from the ROSE trial is 51%. If you multiply these two, you end up with about 50 milligrams per deciliter difference. If you put that number on the CTT meta-regression line, you end up with about a 25% drop in MACE. That is, of course, a very, very clinically relevant result, but we will have to execute on the trial. Make sure it's long enough, it is with adequate enrolment, the patient have high enough risk. That is the task that now lies before us.

My conclusions are that driving statins to their highest dose as monotherapy has many downsides of which failed goal attainment is the worst. I've shown you emerging data to support options like combining early with ezetimibe, with bempedoic acid, with monoclonals, with inclisiran that make a lot of sense. I've also shown you that there are agents around the corner such as the CETP inhibitor, obicetrapib, and what I haven't shown you, but I tell you now, there are oral PCSK9 modulators that are in the clinic. Both have shown promising results today. Thank you very much.

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