[00:00.8]
My name's Steve Nicholls, I'm professor of Cardiology at Monash University in Melbourne, Australia. And I'm talking about the pooled MACE data for the CETP inhibitor, obicetrapib.

[00:15.0]
Obicetrapib is a CETP inhibitor that's an important factor involved in lipid metabolism. We've demonstrated in early studies that obicetrapib reduces levels of LDL cholesterol and lipoprotein(a), on top of statin therapy.

[00:31.5]
And what we wanted to do in this analysis was to take two of the phase 3 lipid studies and ask the question: were there less major adverse cardiovascular events in patients treated with obicetrapib compared with placebo? Pooled analysis includes two clinical trials, the BROOKLYN study, a study of 354 patients with heterozygous familial hypercholesterolemia with high levels of LDL cholesterol despite use of statin therapy, who were treated with obicetrapib or placebo for 12 months, where the primary endpoint was looking at lipids and lipoproteins.

[01:10.0]
And then the BROADWAY study, a similar study of 12 months comparing obicetrapib and placebo, but this time in more than 2,500 individuals, high cardiovascular risk, and that was defined as either the presence of ASCVD or the presence of heterozygous FH.

[01:28.5]
And then what we did was we pulled the MACE outcomes from those findings. This is a relatively small cohort. It's a relatively short follow-up. We do have a very long cardiovascular outcome trial called PREVAIL, involving more than 9,500 patients that's ongoing.

[01:47.5]
But we wanted to do this analysis now to ask the question: could we get an early look? And is there any early signal of potential MACE benefit with obicetrapib? So the key outcomes, firstly, we see less cardiovascular events in the obicetrapib group.

[02:05.3]
Despite the fact that this is small and it's only 12 months, we see a hazard ratio in the order of 0.68 in favour of obicetrapib for the combination of coronary heart disease death, myocardial infarction or coronary revascularisation, suggesting that cardio coronary events seem to be favourably impacted relatively early.

[02:28.1]
The second thing we observed was when we looked at the cardiovascular events in the first 6 months of that period and the second 6 months of the period, all the benefit was later on, and in fact the hazard ratio in favour of obicetrapib from month 6 to month 12 was 0.45, suggesting that now there was more than a 50% reduction in cardiovascular risk.

[02:52.3]
Now these are small cohorts. These are relatively short time of follow-up. We see the same LDL and Lp(a) lowering that we've seen previously in the programme. But it does give us some hope that the big outcome trial that we have ongoing may lead to cardiovascular benefit.

[03:17.0]
And then the final observation was that when we looked at the relationship between lipid levels and cardiovascular risk in the study, we saw a direct relationship between higher levels of LDL, higher levels of ApoB, higher levels of Lp(a) and lower levels of HDL cholesterol, all associating with higher cardiovascular risk.

[03:39.8]
So the factors that we know associate with harm are still there in the setting of this CETP inhibition. So altogether, encouraging signs continues to build the story of obicetrapib potentially being quite a useful therapy in the prevention clinic.

[03:59.3]
What we've been able to demonstrate in all of the clinical trials of obicetrapib conducted to date, and what's important in terms of its implications for the clinic, are that this is an agent that's very effective at lowering LDL cholesterol. Turns out it's pretty effective at lowering Lp(a).

[04:16.0]
It's well tolerated by patients. We now have an early signal of cardiovascular benefit that will need to be validated in a much larger ongoing clinical trial. But if you put all of that together that sounds like a pretty useful therapy that patients who can't get to goal may be able to use in the not too distant future, so it gives us another tool in the lipid lowering toolbox that hopefully will come to a clinic in the next year or two.

[04:46.5]
The CETP space has been really complicated for many years. There's been an enormous amount of enthusiasm and hope that CETP inhibitors would be cardio protective. We've been looking at these therapies for more than 20 years, but when we first started looking at them, we thought it was about raising HDL cholesterol.

[05:04.7]
Turned out that wasn't the solution. When we've gone back and looked at the trials that have been done before of previous agents, any potential benefit was related to having lower levels of LDL cholesterol. And why that's important is it complements the genetic studies.

[05:21.3]
The genetic studies tell us that if you have low CETP, it's cardioprotective, and that that cardio protection is driven by having a lower LDL. So as we then embarked on developing the obicetrapib programme, we did it completely differently than had been done before.

[05:39.9]
We thought, let's focus on the ability to lower LDL. Let's make sure that we've got a therapy that's really good at that, which we do. Turns out it's pretty good at lowering Lp(a) as well. But then let's design a cardiovascular outcome trial of high risk patients who have high LDL cholesterol levels, because they are the patients that still need lipid lowering therapies and in whom we think the biggest benefit will be seen.

[06:07.0]
So we think we've got the right agent, we've designed the right trials in those development programmes, we've learned a lot from the trials and the therapies that have gone before. Now we just have to wait for more trials to report out, but the data we're presenting at the ESC with the pooled MACE data is another exciting, supportive chapter in the obicetrapib story.