So what have we learned from previous clinical outcome trials with CETP inhibitors? We have the luxury that we've had four large cardiovascular outcome trials of different CETP inhibitors and they've given us different pieces of information.

The first of these trials was with an agent called torcetrapib. This was a large cardiovascular outcome trial of about 15,000 patients, who either had clinically manifest ASCVD or at high risk. With the agent torcetrapib compared with placebo, on top of statin therapy. And while there was a lot of excitement about the potential for this agent, the study was stopped early. It was stopped early due to the signal of an increased rate of all-cause mortality by 58% and a 25% increase in cardiovascular events. Now when we went back and looked at that study, we identify that there were a number of off-target pharmacological effects of torcetrapib. We knew there was an increase in blood pressure, there was a number of electrolyte abnormalities. They were very consistent with activation of the renin-angiotensin-aldosterone system, in addition to a range of other off-target effects that we've seen in preclinical models. And what that told us was that it might be that off-target effects, may very much have contributed to the adverse clinical effects we saw with torcetrapib.

So if we could develop another CETP inhibitor that lack those types of effects then it might still be worthwhile to pursue as a cardioprotective agent. That was the rationale for dalcetrapib. Dalcetrapib was a much more modest CETP inhibitor. The dal-OUTCOMES trial enrolled about 16,000 patients with a recent myocardial infarction and randomized patients to treatment with dalcetrapib or placebo, in addition to standard of care which was intensive lipid-lowering therapy. Here you see the increase in HDL cholesterol in the dalcetrapib group compared to placebo. Much more modest compared to what we see with the other CETP Inhibitors. Importantly, this modest CETP inhibitor has no impact on LDL cholesterol. And here you see the LDL cholesterol levels throughout the dal-OUTCOME trial. No difference between the dalcetrapib and the placebo groups. And again another study that stopped early. This time not due to toxicity but due to clinical futility. We see no difference in cardiovascular event rates between patients treated with dalcetrapib or placebo. So it was obvious that the HDL increase in dal-OUTCOMES did not lower the CHD risk.

What's the third study? The third study is the ACCELERATE study and that looks at a more potent CETP inhibitor evacetrapib. And in this study, we enrolled 12,000 patients with a recent acute coronary syndrome or other forms of atherosclerotic cardiovascular disease. They were randomized to treatment with evacetrapib or placebo, in addition to standard of care lipid-lowering for their high cardiovascular risk. Here, you see the baseline demographics. In the study, importantly, we saw LDL cholesterol lowering in the evacetrapib group compared to placebo. But probably overstated the degree of LDL cholesterol lowering we saw, because they used probably an assay that is less than ideal to be measuring LDL cholesterol in the setting of treating patients with a CETP inhibitor. And again, we have the third study somewhat disappointing again, that stopped early this time again for futility.

So we have a modest CETP inhibitor with dalcetrapib that stopped early for no clinical effect, we have a more potent CETP inhibitor with evacetrapib. With patients treated for a little over two years where we see no clinical benefit. And that two-year point is a really important point because if you go back and look at the IMPROVE-IT study, where we saw the benefits of ezetimibe compared with placebo on top of statin therapy. While there was a clinical benefit in that study, it took time before the curve started to separate. In fact, it really took the better part of two years before there appeared to be any suggestion of a difference in events between the two groups. And the LDL cholesterol lowering that we see with ezetimibe and IMPROVE-IT it is not dissimilar to probably what the real LDL cholesterol lowering is with evacetrapib. So it's possible that in the ACCELERATE study we simply didn't follow patients for long enough.

The fourth outcome trial gives us some ray of hope. The REVEAL was a very large study of more than 30,000 patients. They had occlusive vascular disease. Again they were randomized to treatment with the potent CETP inhibitor anacetrapib or placebo in addition to background lipid-lowering therapy. This is the worldwide study and importantly patients in this study were treated for a much longer period of time. The idea was that patients were going to be followed for at least four years. With the idea that the REVEAL investigators would look at a large number of cardiovascular events. Again, you see similar LDL cholesterol lowering and ApoB lowering in the anacetrapib treated patients, as we had seen with evacetrapib in the previous study. But where this study differs is that we see a significant reduction in cardiovascular events. We see a significant benefit, albeit modest with a reduction in the number of events in patients treated with anacetrapib compared with placebo. And importantly, when we went back and looked at the relationship between changes and lipid parameters and cardiovascular benefit in this study, it had nothing to do with the increase in HDL cholesterol. In fact, it was the reduction in non-HDL cholesterol... that completely predicted the benefit that we saw with anacetrapib suggesting it was a reduction in the atherogenic lipid factors and not an increase in the protective lipid factors, that may have contributed to the benefit we saw in that study. Then finally on longer term follow-up in the REVEAL study, we've seen that patients treated for longer and even following the study when patients had come off study drug, the difference in event rates between the placebo and the anacetrapib group continues to actually be greater. And so, it's potentially not just about using a potent CETP inhibitor. Not just lowering LDL cholesterol or non-HDL cholesterol but doing it for as long as you possibly can, gives us the best chance to reduce cardiovascular risk, and that gives us a lot of food for thought, as we designed the cardiovascular outcome trial for the obicetrapib program.

So let's review the clinical trial program for obicetrapib. First of all, there's the TULIP study. This was reported in the Lancet in 2015. And TULIP was an important lipid lowering study and it established for the first time that not only administration of obicetrapib was well tolerated by patients, but you saw about a 45 percent reduction in LDL cholesterol levels, which was pretty comparable between the 5 and 10 milligram doses. The more recently reported ROSE study, this was an important trial because it looked at the impact of 5 or 10 milligrams obicetrapib added to high-intensity statin therapy with patients treated for eight weeks and we saw about a 50% lowering of LDL cholesterol. It was better with the 10 milligram dose compared with the 5 milligram dose. Agent again was well tolerated by patients and it gave us the information that we needed to move forward with 10 milligrams, being the dose that we would carry forward in other clinical trials.

What's ongoing today? The ROSE2 study. ROSE2 was important because it looks at patients again treated with high intensity statin therapy and LDL cholesterol of at least 70 milligrams per deciliter, and it will look at three treatment groups placebo, obicetrapib 10 milligrams, or obicetrapib 10 mg added to ezetimibe. So, we'll see what the combination of the CETP inhibitor and a cholesterol absorption inhibitor do in these patients.

Two very large lipid studies, that are ongoing in the obicetrapib program. First of all you've got BROADWAY. BROADWAY is a study of 2400 patients who were treated with maximally tolerated lipid modifying therapy. They are required to have an LDL cholesterol of at least 100 milligrams per deciliter or an LDL cholesterol between 70 and 100 milligrams per deciliter. Provided, they have at least one additional cardiovascular risk factor. So these are higher CV risk patients treated appropriately with maximally tolerated therapy and we're going to treat them for 12 months. It will give us a lot of safety and tolerability data. We'll look at the primary endpoint early at 12 weeks, this is an important next step in this program. And then it's parallel study, the BROOKLYN study, a study of 300 patients. This is a study of patients with documented heterozygous familial hypercholesterolemia. Again, all of these patients were on maximally tolerated statin therapy, and they're required to have an LDL cholesterol of at least 70 milligrams per deciliter at study entry. So, these studies are really important because they're going to evaluate the impact of obicetrapib in addition to maximally tolerated statin therapy in higher CV risk patients who have not yet reached their LDL cholesterol goal.

And it's a really important series of safety, tolerability, efficacy studies moving forward and that leads us ultimately to the cardiovascular outcome trial the PREVAIL study. This is a study that we've just recently launched and started to recruit. It is a study of 9,000 patients. These are patients, that will all have established atherosclerotic cardiovascular disease, they will be treated appropriately according to national guidelines with maximally tolerated lipid modifying therapy and they will be required to have an LDL cholesterol between 70 and 100 milligrams per deciliter with at least one additional risk factor or to have an LDL cholesterol greater than 100 milligrams per deciliter. So again, this is an important study but unlike the other studies where we're looking at the effect of obicetrapib on lipids. In this study, we're going to look at the impact of 10 milligrams of obicetrapib in addition to standard background maximally tolerated lipid-lowering therapy on the composite major adverse cardiovascular endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and urgent coronary revascularization. Putting all the information that we've learned about CETP biology and genetics, all the lessons learned from the prior cardiovascular outcome trials of other CETP inhibitors, we've been able to develop a CETP inhibitor that is potent in terms of its ability to lower LDL cholesterol, we designed a clinical trial that is all about patients who have an unmet need of sub-optimally controlled LDL cholesterol, who are at high CV risk. We believe it's the right study to ultimately question once and for all: will a CETP inhibitor lower cardiovascular risk? The PREVAIL study has the best opportunity to give us that answer.

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