Hi, I'm Dr. Erin Michos, I'm the associate director of preventive cardiology at Johns Hopkins University in Baltimore, Maryland, United States. I'm very excited to be here at the European Society of Cardiology meeting on behalf of PACE-CME. Today I'll be talking about novel oral pathways in LDL lowering therapy, the new promise of CETP inhibitors. These are my disclosures.

Just a reminder that cholesterol ester transfer protein promotes the transfer of cholesterol esters from the anti-atherogenic HDL to the pro-atherogenic LDL particles. Inhibition of CETP, raises HDL and lowers LDL. CETP activity increases circulating LDL levels, and therefore contributes to LDL buildup in the arterial walls, and that's why inhibition of CETP is an attractive strategy for LDL lowering. I think CETP inhibition got a lot of attention for its potential in HDL raising, but just a reminder that CETP inhibition can lower LDL and lower ApoB. This is because inhibition of CETP decreases hepatic cholesterol concentrations, and this leads to upregulation of the LDL receptor on the surface of the liver, and clearing LDL out of circulation.

Now, there is genetic evidence from Mendelian randomization studies, really showing that CETP may be causally related to atherosclerotic cardiovascular disease that we see. That a 16% reduction in cardiovascular risk is observed with every 10 milligrams per deciliter of lowering of LDL in patients with loss of function in the CETP genotype. This is really equivalent to the level of cardiovascular risk reduction observed in patients with loss of function in other genes, such as loss of function and HMG-CoA reductase, which is the target of statins with loss of function of PCSK9, and loss of function of the NPC1L1 genotype, which is the target of ezetimibe. In other words, regardless of mechanism of action, the same absolute lowering LDL cholesterol translates to reduction in cardiovascular risk.

Again, it was not initially appreciated that the loss of function mutations seen in CETP, not only lead to increases in HDL cholesterol concentration, but also to lower levels of LDL, non-HDL and ApoB and so we now have a better understanding that inhibition of CETP lowers cardiovascular risk, not by raising HDL, but by lowering these atherogenic lipids and lipoprotein concentrations.

This slide shows the previous history of the CETP inhibitors. The first agent studied torcetrapib was evaluated in the ILLUMINATE trial. This agent did lower LDL cholesterol as well as raising HDL, but unfortunately, the trial was terminated early due to increases in cardiovascular events and increased death. Then we came to the understanding that this agent actually has off-target effects. It increases aldosterone. It increases blood pressure, and that's what led to the adverse cardiovascular outcomes. That mechanism is independent or unrelated to the CETP inhibition. It really is specific to this compound as an off-target effect. The next agent that was studied dalcetrapib did raise HDL, but really had a weak to very little LDL or ApoB lowering, and Dal-OUTCOMES trial was terminated for futility. This was really the end of the HDL hypothesis, because we had this significant increase in HDL, and there was no reduction in cardiovascular events. Now, the next agent studied was evacetrapib, and this did lower LDL cholesterol, but the study had some issues. First of all, the LDL was fairly well controlled in the study, so it was really underpowered for outcomes and it was terminated early at only 26 months. We know from other studies, like the IMPROVE-IT study with ezetimibe, that you really need to follow individuals for a longer period of time to see the benefit. It was stopped too soon before a benefit could be demonstrated. The next agent, anacetrapib was the only one that did have a positive cardiovascular outcome trial. There was a 9% reduction of MACE at the original median follow-up of 4.1 years and with additional follow-up of additional 2.3 years, we actually saw further benefit of 20% reduction. There was some initial misunderstanding about how much LDL lowering was seen with anacetrapib. With these LDL levels being well controlled, the trial had used direct LDL assay, which really doesn't work very well at very low LDL levels. It was initially reported that there was a 41% reduction in LDL, but when you actually use the beta-quantification assay, we see a 17% reduction in LDL. If you were to plot that on the line of the cholesterol treatment trials, this 17% reduction or about 11 milligrams per deciliter of LDL lowering, really falls right on the line of MACE reduction that you would expect to see for that degree of LDL lowering. Here is the data from the REVEAL trial with anacetrapib. Again, as mentioned, at 4 years of follow-up, we see a 9% reduction of MACE, but the curves continue to widen so that at 6.3 years, there's actually a 20% reduction in MACE. Again, confirming a cardiovascular outcome of reduction with CETP inhibition.

Then we have the next generation of CETP inhibitors. Obicetrapib is a much more potent CETP inhibitor, has a greater efficacy at inhibiting CETP activity than anacetrapib or evacetrapib. The ROSE study evaluated obicetrapib 5 milligrams and 10 milligrams of oral medications compared to placebo on a background of high-intensity statins at eight weeks of follow-up. What we see is that there was a 51% reduction in LDL lowering when using the ultracentrifugation assay. If you were to use the friedewald estimation, you see a similar 46% reduction at the highest dose. We also see a 30% reduction in ApoB and a 44% reduction in non-HDL with obicetrapib 10 milligrams. There was a 57% reduction in lipoprotein(a) and there was also some reduction in triglycerides, although this was a little bit more inconsistent.

In summary, obicetrapib both the 5 and 10-milligram doses, were well tolerated on top of high-intensity statins with about 50% reduction in LDL at the highest doses. The LDL lowering was comparable at all baseline levels of LDL lowering and wasn't mitigated by combination with high-intensity statins. This really has now emerged as the potential to be a viable addition for high-risk ASCVD patients who need additional LDL lowering despite maximally tolerated lipid therapy. Then the ROSE2 trial, which was recently presented, evaluated obicetrapib 10 milligrams or in combination with ezetimibe compared to placebo at 12 weeks. What we see is that the combination obicetrapib/ezetimibe, now we get a 63% reduction in LDL cholesterol. This is really the equivalent of what we're seeing with the monoclonal antibodies for PCSK9 injectable medications and yet we can get the same reduction in LDL with an oral medication pill. In ROSE2 trial, 87% of patients taking the combination obicetrapib/ezetimibe got to those very intensive LDL targets of less than 55 milligrams per deciliter. There was no significant treatment-emergent adverse events. In fact, these adverse events were actually numerically fewer in the obicetrapib arms compared to placebo so the safety data looks really good.

In conclusion, the combination of obicetrapib and ezetimibe can achieve LDL lowering in the range of 63% on top of high-intensity statins as well tolerated and this gives rationale from moving on to the phase three trial, which is PREVAIL. PREVAIL is a cardiovascular outcome trial enrolling 9,000 patients with established ASCVD who either had LDL cholesterols of 70 to 100 and at least one additional risk factor or LDLs remain above 100 despite maximally tolerated lipid therapy. It's an event-driven trial. Then we'll see whether this potent LDL-lowering agent can translate into meaningful cardiovascular events.

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