LDL-c lowering with CETP inhibitor in patients on high intensity statins

Hello, friends. My name is Kausik Ray from Imperial College London and I'm going to talk about the results of a very exciting study called the ROSE Trial. What was the ROSE Trial? Well, ROSE evaluated two doses of obicetrapib, a CETP inhibitor, and LDL-lowering in patients receiving high-intensity statins. These are a list of my disclosures.

So why do we need additional therapies? Very simply, the new guidelines as they've moved to recommend lower cholesterol goals, inevitably mean that although high-intensity statins are always going to be first line treatment about 80 percent of patients will not get to goal. This means that new treatments are going to be needed. Now, if you look at the current options with add-on oral lipid-lowering therapies the best that you can get is about another 25 percent lowering in LDL cholesterol. Now, you might say, well there are injectable therapies. Yes, there are and they do provide profound reductions, but cost has limited their uptake and availability. As a result of that, there is a high unmet need in the general population where the bulk of our patients sit. I.e. on top of high-intensity statins, we need another option. So, we know from genetic studies that CETP inhibition as a target is valid. We know that this associates not only with lower LDL cholesterol levels, but also lower risk of cardiovascular events. And we know from randomized control trials that pharmacologic inhibition of CETP not only results in LDL lowering but also cardiovascular events in the magnitude of that LDL lowering predicts the cardiovascular events.

So to date, although there has been potential the efficacy or the safety profile of early generation CETP inhibitors have halted their development. Now, obicetrapib is a CETP inhibitor that has been evaluated in earlier studies but on a background of low, or no dose statin therapy. There it reduced LDL cholesterol by 45 percent. So the objectives were in this study to evaluate two different doses, 5 and 10 milligrams of obicetrapib and assess their efficacy on LDL-lowering as well as safety and tolerability. But now on a background where everybody received high-intensity statins.

This slide shows the trial schema. Patients were randomized to placebo or obicetrapib 5 milligrams, or 10 milligrams. The primary efficacy endpoint was LDL lowering at eight weeks with further safety data available through to 23 weeks. The patients all received high-intensity statin therapy and they were required to have an LDL above 1.8 millimoles or 70 milligrams per deciliter, despite this. The exclusion criteria are also shown and the primary efficacy endpoint is LDL lowering. But we're obviously also interested in other atherogenic lipids and also goal attainment.

This shows the patient disposition, the numbers screened and trial completion. So 195 patients were screened. 120 were eventually randomized in three groups: 40 to placebo and 40 each to 5 and 10 milligrams of obicetrapib, respectively. So 119 patients completed treatment.

I'm going to show you the data as per an ITT population. These are the baseline characteristics and as you can see, consistent with all of these sort of studies the average age is approximately sixty. There are greater proportion of women than in most clinical studies. And this is of the order of about 40 percent. Now, BMI is relatively high and this study was conducted in North America. So you have a mixture of white and African-American populations as well. As you can see, everybody received high-intensity statins defined as 40 milligrams or 80 milligrams of atorvastatin or rosuvastatin, 20 or 40 milligrams. The baseline LDL cholesterol was around 90 milligrams per deciliter. So again, this is a population with a high unmet need. Respective LP(a) and HDL cholesterols are also shown for completion.

Now this is the primary endpoint and LDL lowering was evaluated in two ways. In the classical way which is using the Friedewald formula to calculate LDL and this showed dose-dependent reductions in LDL with the top dose achieving 46 percent lowering. With ultra-centrifugation we basically were able to show again in a dose-dependent fashion a 51 percent lowering of LDL cholesterol was achieved. As you would expect, when you look at people with higher and lower baseline LDL cholesterol, the effect is consistent. So there is no difference effect based on starting levels of LDL. The drug works equally well. And if we look at the distribution of LDL cholesterol in the individual responders with the waterfall plot you can see that everybody actually gains further reductions in LDL cholesterol. I want to also point out that you can see in the placebo group individual patients go up and down between the two time points. This is happening in the background of the obicetrapib treated patients. So there is really no variability in response when you account for this.

So everybody should have consistently, if adherence is perfect, something approaching 50 percent lowering of LDL cholesterol. Now, if we look at other atherogenic parameters you can see, again in a dose-dependent fashion, ApoB was reduced by 30 percent. And you can see that you have reductions in non-HDL in the mid fourties. So these are consistent with what you would expect for the reductions that we have observed in LDL cholesterol. For completion, you see large increases again in a dose-dependent fashion in HDL cholesterol with significant increases in ApoA1. Interestingly, there are reductions in lipoprotein(a) approaching about 50 percent again in a dose-dependent fashion. You can see modest changes in triglycerides consistent with other therapies that are non-triglyceride specific. The most important thing that addresses the unmet clinical need is this. And these are basically graphs showing goal attainment with the height of the graph showing the different levels of goals that are achieved cumulatively for LDL, non-HDL cholesterol and ApoB.

So if you look at patients achieving for example 70 milligrams per deciliter of LDL, 100 milligrams per deciliter of non-HDL or 80 milligrams per deciliter of ApoB. About 90 percent of our patients can get to these goals if we were to add in obicetrapib at the higher dose on a background of high-intensity statins.

When we look at the safety data we can see that there is nothing to see here. That basically adverse event profiles are equally balanced between the treated group and the placebo group. SAEs, again, there were none in the obicetrapib treated population. And there were no study drug withdrawals.

So in summary, I started with the question about the high unmet need and whether this therapy could be a potential solution. Obicetrapib in a dose-dependent fashion, on top of high-intensity statins firstly was well-tolerated and for a study at this stage, that is really important. Now, the two doses that were studied as far as efficacy was concerned provide significant additional reductions in LDL cholesterol of 42 or 51 percent from baseline, respectively. So that is five and ten milligram doses. Now, these reductions are consistent. Irrespective of background LDL cholesterol levels. There are also important dose-dependent reductions in other atherogenic lipoproteins, non-HDL, ApoB and LP(a). And the most important thing, the unmet need, is that if we use this potential as an add-on to high-intensity statins the vast majority of our patients will achieve the different atherogenic, lipid goals. What is exciting now is that this drug is ready to go into the next stage. So obicetrapib is currently being evaluated in phase 3 Lipid Lowering and important in cardiovascular outcome trials. And when these complete, they could be a valuable addition for high-risk CVD patients who currently don't achieve the guideline recommended goals despite taking first-line therapy, which is high-intensity statins.

Thank you for listening.