Prof Julian Halcox, Professor of Cardiology, Swansea University College of Medicine, UK, speaks with Cardio Debate & Radcliffe Cardiology about Advances in the Management of Dyslipidaemia (Part 1 of 3 interviews), during the 2015 Cardiovascular Sciences Research Centre Annual Meeting held at the Royal College of Surgeons of England in London, UK.
Familial hypercholesterolaemia: Role for PCSK9 inhibitors
I think the PCSK9 story is really interesting. At its root it came from the observation that a small protein – proprotein convertase subtilison/kexin type 9, PCSK9 – was associated with an influence on LDL receptor biology and also circulating levels of LDL. So individuals who have genetic variations that produce more or less of the PCSK9 have different levels of circulating LDL.
So the PCSK9 is a little protein that targets the LDL receptor, and when this is internalised, when it is bound to LDL into the liver cell, the vesicle that has the PCSK9-tagged LDL receptor, LDL complex, is going to be broken down and turned over, and there will be less of the LDL receptor to be recycled to the surface.
So when there are lower levels of PCSK9 there is less internal degradation of the LDL receptor, meaning that there are more of these receptors recycled to the surface for further clearance of LDL.
So these genetic variations that led to differential LDL levels due to the differential levels of PCSK9 were associated with substantially different cardiovascular outcomes.
With the individuals with the PCSK9 variations that were associated with the lower LDL cholesterol over the course of the individual’s life, they have much, much lower incidence of myocardial infarction.
So if genetic variations in this could actually make a difference the question clearly is can we do something to expression or levels of this PCSK9 that might actually reduce LDL receptor turnover and lead to lower levels of LDL through enhanced LDL receptor mediated clearance, and hopefully translate into better outcomes.
Now there have been a few agents that have been developed – and three are in fairly advanced stages of clinical development, having gone through phase 3a studies and are now into phase 3b – which have shown that there are quite substantial benefits on LDL levels.
Now these agents are monoclonal antibodies that target PCSK9, and rather than with the genetic variations that produce less they actually target the PCSK9 and stop it binding to the LDL receptor. So when there’s less of this PCSK9 receptor interaction the LDL receptor lifespan is far greater, it can be recycled and taken back to the surface – its retention is greater and has a greater effect on LDL levels.
Now in the doses that have been studied we can see fairly dramatic effects on LDL levels, which can go down by about 50 to 60 per cent. And there have been relatively short-term phase 3a studies – 1 year, 18 months – in high-risk groups with familial hypercholesterolaemia and individuals at high cardiovascular risk whose LDL levels are still high despite maximum tolerated doses of statins, with fairly consistent benefits on LDL.
But what is really interesting from the pooled analysis of these data, both from the Amgen agent evalocumab, and the Sanofi agent alirocumab, that over the course of one year these dramatic reductions in LDL seem to be associated with dramatic reductions in cardiovascular events, even within that short time-frame.
Now of course there’s only a few thousand patients been studied for one year, 18 months, so it’s a little bit early to get too excited and to expect that these are agents that are ready for use in all of our high-risk patients who aren’t at target despite statin therapy. But it certainly is a very exciting initial observation, and one would hope that this translates into significant benefits in the long-term studies.
So I think at present two of these agents are now licensed – alirocumab and evalocumab – and NICE is going through the appraisal process to see whether this is something that is going to be cost effective for use, and we’ll have to wait and see exactly where they come down.
But I think certainly for these very high-risk patients who have very high levels of LDL despite maximally available treatment have a very high lifetime risk of cardiovascular disease, specifically these FH patients. I think there’s, even now, there’s a call for use of these agents in our routine practice.