Novel LDL-c lowering therapies: What is the potential for ANGPTL3 inhibition in HoFH?

I'm going to discuss novel lipid LDL-C lowering therapies. What is the potential for ANGPTL3-inhibition? This is my disclosures.

And I thought I'd start with a case of a young patient. A miss A-R 16 year old female. The parents noticed yellow lumps over her hands, elbows and buttocks. And as a result of the lipid profile which is shown here, a very markedly elevated total cholesterol and LDL-cholesterol level. This is a picture of her hands and when you see this you need to think about a diagnosis of familial hypercholesterolemia, particularly homozygous familial hypercholesterolemia.

This is a codominant condition. If you inherit it from one parent, your cholesterol levels are about twice normal and you have heart attacks starting in your 30s or 40s. The much more severe condition is homozygous FH where the cholesterol LDL cholesterol levels are about four times normal and heart attacks begin in childhood. We know a lot about the genetics. It's mainly due to mutations in the LDL receptor and this young patient was found to have two mutations in her LDL receptors.

So, she was a true homozygous FH patient. However, we know these days there's an overlap between heterozygous FH and homozygous FH. The less the receptor functions, so those homozygous patients that have null or very little residual LDL receptor function have the highest LDL cholesterol levels and the most severe coronary artery disease.

We also know that the LDL cholesterol that we can obtain or achieve determines outcome. So the lower the LDL cholesterol level that we can achieve in these patients, the better. There are various therapies and I am going to concentrate on the lipid-lowering drugs, the new lipid-lowering drugs for these difficult to treat patients. And they can be divided into two categories: the LDL-receptor dependent drugs and the LDL-receptor independent drugs.

So, we know that statins are our standard therapy. And even though we don't have an outcome study, all our patients with severe hypercholesterolemia are on statins. They work by upregulating the LDL receptor. So they're LDL receptor dependent and we must not forget that they do work in homozygous FH patients. They are about half as effective but we can get a 25 to 30 percent reduction in LDL cholesterol with statins in homozygous FH patients. Interestingly, they even work in homozygous patients with zero or null receptors. And we think the mechanism, which I'll discuss later, is because we inhibit ANGPTL-3 production via LXR within the liver.

We can add ezetimibe, which will result in another 20% or so reduction, even in homozygous FH. And so this is the lipid profile with a combination of high-intensity statin and ezetimibe. In this young patient the levels did come down but you can see they're still remarkably elevated.

What about inhibiting PCSK9? Would that work? And there's a lot of studies to show that PCSK9 inhibition in homozygous FH patients is about half as effective once again. So instead of a 60% reduction in LDL cholesterol we get a further 30% reduction but this is very dependent on LDL receptor function. So the true negative homozygous do not respond to this therapy, but if you have some residual LDL receptor function, you do respond. And this therapy is effective in the long term. This is four year data showing that you can get a persistent reduction in LDL, but it's only about half as effective as in heterozygous patients. And as indicated here, the ones that are receptor negative, the null patients, don't respond very well. So this patient was involved in the trial, we added a PCSK9 monoclonal antibody and as a result the LDL did reduce further but still very high for this young patient.

So what about the newer exciting therapies that are LDL receptor independent? And there's really two classes: lomitapide and the new drug ANGPTL 3 inhibitors. So just to say a few words about lomitapide, it prevents the formation of VLDL and that's LDL in the liver. They are as effective in reducing LDL by about 50%, but the price we pay is that you get a fatty liver, they're response is variable, it's a difficult medication to take and with time you get an accumulation of fat in the liver.

So what about ANGPTL3? Which is called Angiopoietin-like 3 and appears to play a central role in lipid metabolism. The genetic evidence supports the fact that at this reduced cardiovascular disease, is associated with low triglycerides, LDL as well as HDL levels and animal models support the use of this drug because you can inhibit atherosclerosis. So, there was an early proof of concept study just in nine patients, which showed that this drug was effective in homozygous FH patients with about a 50% reduction in LDL cholesterol. This was a proof-of-concept study done by Daniel Gaudet, but I was involved in the bigger study, the placebo-controlled study, called the ELIPSE study. We enrolled about 65 patients and evinacumab which is given as an infusion. It is a monoclonal antibody against ANGPTL3. 15 milligrams per kilo gram given monthly reduced LDL cholesterol by about 50% in this study. Importantly, it worked just as well in those patients with no LDL receptor function at all. What we would call null null patients as those with some residual LDL receptor.

So how does it work? We're not a 100% sure. But we do know that we elevate lipoprotein lipase activity and very important endothelial lipase activity. So it's upstream from the LDL receptor, does not depend on LDL receptor function. So we gave our patients evinacumab and she achieved a remarkable reduction in her LDL cholesterol level. So this is just the time course, from a very high level of 14.6 we got her LDL cholesterol level down to 2.2. So, the type of drug we use depends very much on LDL receptor function, but this new drug, the ANGPTL3 Inhibitors, which are LDL receptor independent is an additional drug that we can use to treat these very difficult to treat patients.

So, it's going to be an added drug in the algorithm for treating homozygous FH patients. We're going to add it on top of our other therapies. Is this a cure for homozygous FH? In terms of Gil Thompson's words: Like conquering Mount Everest, overcoming the challenge of homozygous FH has been a very long and difficult endeavor. But with the arrival of novel drugs, like these ANGPTL3 inhibitors, I do hope we will have a cure for this difficult to treat condition.

Thank you very much.