Dr Christie Ballantyne:

Hi, I'm Christie Ballantyne. I'm the Chief of Cardiology and Cardiovascular Research and the Director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine in Houston, Texas.

What is the current treatment landscape for patients with heterozygous familial hypercholesterolemia, and where do oral PCSK9 inhibitors fit?

Well, this has been an exciting meeting about where we stand for PCSK9 therapy because we had a late-breaking study this morning called VESALIUS. And we knew that there was benefit in secondary prevention, but this showed very strong benefit in high-risk primary prevention.

This was a monoclonal antibody, evolocumab every two weeks, but it had a 25% reduction by the primary endpoint. But what was a really very important thing it showed actually: reduction in total mortality.

So it was exciting news and it further expands the patients that we're thinking about. Not only secondary prevention, not only familial hypercholesterolemia, but also high-risk primary prevention.

What were the primary objectives of the CORALreef HeFH trial?

PCSK9 is really a target that came up from biotechnology because of genetic loss of function variants.

And so it's been fascinating to watch as you had the monoclonals, that's blocking protein, you had the siRNAs blocking protein synthesis, and then there's the development now of a macrocyclic peptide that blocks the interaction of PCSK9 with the LDL receptor.

So it's a big, small molecule that works like a monoclonal; it blocks those two proteins from interacting with each other. So there were two studies presented at this meeting. The name of the molecule is [illegible]. I was the PI.

One of them is with heterozygous FH. We know that's an important patient population. The other one is people with high-risk, primary prevention. But both of them show there was very good efficacy; similar to the phase two studies, around 60% LDL reduction and very good reductions in non-HDL cholesterol, around 52%; ApoB, about 50%; and also lipoprotein A, around 27, 28%.

What was the study design and key findings?

So there are two phase three lipid studies. There has been a phase two dose-ranging study, looked at various dosage, but it was short term, only about 12 weeks. And it showed that you got about a 60% reduction. So these looked at the dose and they carried it forth into a phase three program.

Two important patient populations. So one is heterozygous, the medial hypercholesterolemia. And this study enrolled, it's a 2:1 randomisation. It was about 300 participants, 12 months of follow up. Always important, you want to see what's the duration? Does the therapy keep working?

And then also for side effects, you need a longer duration and also bigger numbers. The second study, and that was called [illegible] lipids and it was looking at high-risk individuals, a mixture of secondary prevention, high-risk primary prevention. Same design of 2:1 randomisation, but now a bigger study, about 2,900, so closer to 3,000 patients.

About almost 10 times as big and also again with one year of follow up. Showed very similar results in regards to the [illegible] that was about 52%, ApoB was about 50% reduction.

Good reductions in LDL cholesterol in that study also. So very concordant data and both of them show good safety profiles. Basically, the discontinuations due to adverse events were the same or less than placebo numerically in both studies.

Didn't see any big warning signals in regards to things that we might have worried about like liver function test or muscle problems. So very encouraging in terms of the data we have about the, at least the lipid efficacy for this therapy.

What are your key take-home messages for clinicians managing patients with familial hypercholesterolemia?

So I think if we look at this core reprogram, we get two trials and one thing you always want to see is, are the results concordant? Hopefully you're going to see things confirmed in one study versus another study. So they confirmed the phase-two data.

Two different patient populations, longer studies, larger studies, seeing the same kind of efficacy, no new safety signals. And importantly, there is a large outcomes trial with this agent that's also fully enrolled. So it's always nice to know that there's more safety data accruing and that will have outcomes in it.

It's going to take a number of years though for that study. The study we saw this morning had 4.2 years median duration of follow up. So I think that's what you'll need in those types of studies.

What are the next steps for this research program?

So that study is fully enrolled, but it's going to be a number of years, at least a few years before we have the results of it.