My name's Steve Nicholls. I'm professor of Cardiology at Monash University and the director of the Victorian Heart Hospital.

What is the importance behind the KRAKEN trial?

KRAKEN's important because it's testing the effects of the very first oral drug to lower Lp(a). We know that Lp(a) is an important risk factor for cardiovascular disease. We know that there are currently no therapies approved for lowering Lp(a).

All of the therapies that are currently in clinical trials are injectables and target apo(a) production, and so there's a lot of interest in can we develop an oral drug, and that's what muvalaplin is.

Could you tell us about the mechanism of action behind muvalaplin?

So Lp(a) is essentially an LDL particle with apo(b) that's bound to an APO amoidae. And what muvalaplin does, which is actually quite simple and elegant, it simply blocks the binding. So you end up with an apo(b) particle, you end up with apo(a) that's either by itself or bound to muvalaplin and, therefore, you don't form those intact functional Lp(a) particles.

What was the study design and patient population?

This is a phase two study of 233 patients. They had high cardiovascular risk that was either clinically manifest cardiovascular disease, diabetes or familial hypercholesterolemia; they had to have a high LP(a), at least 175 nmol/L; they needed to be on stable doses of lipid modifying therapies for at least four weeks. And they were treated for 12 weeks with either placebo or muvalaplin at a dose of 10, 60 or 240 mg daily and looking at the effects on LP(a) and other lipid parameters.

What were the key findings?

So we measured LP(a) using two different assays. One's your standard LP(a) assay that you can use in the clinic that measures APO and then a novel assay that measures intact LP(a) particles. And what we found was that 12 weeks of treatment with muvalaplin reduced LP(a) levels by up to 70% using standard assay and by up to 86% using the intact LP(a) assay, which we think is particularly important.

We saw significant reductions in apo(b) by 16%, by LDL cholesterol by 21%, and we saw good safety and tolerability. We also looked at levels of oxidized phospholipids, and that's important because those oxidized phospholipids carried on LP(a) – we think that's what drives atherosclerosis and valve disease. And what we observed was a reduction in oxidized phospholipid levels by up to 73%. So really good effects on LP(a), good effects on LDL cholesterol and apo(b) on top of people who were already being treated with a statin, good lowering of oxidised phospholipids, and very well tolerated by patients.

Were there any surprising or unexpected results?

Here, for the first time, we were going into the types of patients you'd want to treat in the clinic. So we saw better efficacy, which was great. Really good reassuring safety and tolerability, and really sets the scene to now move forward in the not too distant future to a large cardiovascular outcome trial.

What further research is needed in this area, and what are the next steps?

Well the next step, ultimately, is one thing to make the blood numbers look better. Ultimately, will it be better for patients? Will it reduce the rates of heart attack, stroke, revascularisation, cardiovascular death? So there will need to be a large cardiovascular outcome trial in the future. Hopefully we can share more information about that not too soon, so stay tuned.