HoFH: Why is early diagnosis important?

Hello, my name is Kausik Ray, I'm professor of Public Health at Imperial College in London. I want to talk to you about a really important topic and that is homozygous familial hypercholesterolemia.

The need to treat, create awareness, better understanding and insights. And really we should all care about homozygous FH. And I'll show you some data as to why, I'll give you some information as to the background and hope that actually with a change in public health policies and with newer treatments, how we together in the clinician community can make a difference in the lives of these individuals.

These are a list of my disclosures.

I'm going to start with this. So what is homozygous familial hypercholesterolemia? Well, this is a genetic condition associated with very high levels of LDL cholesterol from birth. Now this occurs in about 1 in 300,000 individuals. And this is where both mother and father have passed on an affected gene in the cholesterol metabolism pathway. And as a result of inheritance, it's an autosomal dominant condition. And it's a result of having two abnormal genes from each parent.

We see astronomical elevations in LDL cholesterol from birth. And what does it do? Well, on a superficial level it gives these characteristic cutaneous manifestations, so these xanthomata and we can see them at the classic tendons. But most importantly, what it does is it increases the rate of accelerated atherosclerosis. So imagine in the first decade of life, having aorta with rich in cholesterol deposits. Imagine coronary artery ostium filled with cholesterol that narrow blood flow. Now imagine children potentially having myocardial infarctions or needing a bypass operation or even a liver transplantation, because they have accelerated atherosclerosis, to try to prolong life. The second major manifestation of this is often with supravalvular or outflow tract obstruction and this is basically echocardiography showing aortic root narrowing and also valve thickening. So imagine we think about aortic stenosis as a disease in older people, imagine now somebody within the first or second decade of life, having significant aortic valve narrowing. So that's what the disease does because of this lifelong exposure in LDL cholesterol.

And to try and change public health policy, because this is a rare disease or classified as a rare disease, I was fortunate I lead the FH studies collaboration which is focused on heterozygous familial hypercholesterolemia. But we have homozygous FH patients as well. And we collaborated with the HICC registry, which was focused on homozygous FH to essentially double the world data. And what you can see on this slide are all the countries that collaborated. There are 161 collaborators from 38 countries. And what did we find? And what did we show? Well, we basically collated the largest data set ever of homozygous FH, 751 individuals. The median untreated LDL cholesterol level at diagnosis is 14.7 millimoles per liter. Just as a reminder, a healthy baby without homozygous FH has a LDL cholesterol of 0.5 millimoles per liter. Second most important thing, if you don't screen, you don't find and you can't treat. The average age of diagnosis, I want you to remember this, is 12 ranging from 5.5 to 27 years. And at diagnosis, so by the age of 12, one in ten already had evidence of cardiovascular disease or not just atherosclerotic cardiovascular disease but also aortic valve disease as well. It's really important.

So let's look at what determines outcomes and survival in this condition. Well, it's not really surprising. If we look at tertiles of LDL cholesterol level and here, as a reminder, the lowest LDL tertile ranges from 4.9 to 12.5 and the highest from 17.1 to 36, you can see the higher your LDL cholesterol, the worst your outcomes and survival. So compared to the lowest group, the highest group has a hazard ratio of 3.1. And the median tertile has a hazard ratio of 1.91, so double compared to the lowest.

So, how do we improve outcomes? Well, if LDL determines risks then improvements in LDL will determine outcomes and how do we actually improve LDL? Well, this is not rocket science. This is determined by the number of treatments that you use. So for most non-FH patients, we might be able to get away with one or two drugs. But for people with homozygous FH, this slide shows you the relationship between untreated LDL, and what is achievable in terms of LDL reduction and LDL levels, depending on the number of drugs that you use. So if you look on the y-axis at 5 millimoles to get us to that level, we're going to have to use three, four or five drugs in these individuals, two is not going to be enough. And remember, we're finding these people late.

I want to show you something that gives us a natural experiment and that's the difference between high and non-high income countries. So if you're in a high-income country, you obviously have availability of medications much earlier, and more medications. So what you do in that scenario, is you extend survival. The time to aid your first event is in your mid-30s. If you are in a low-income country, it's in the early 20s. So, basically, having availability of treatment gives you a decade of life or event-free survival. So that's really important in terms of what we can do about policy.

Another important thing is to determine whether these really do make a difference. Now, this is not a randomized trial, but what we've done is we've done a mediation analysis where we've looked at outcomes in non-high income countries. Remember the age of first event is 24 versus those other countries. What are the two things we can change? Well, the first thing we can do is we can basically use three or more medications, and your outcomes are significantly improved. The next thing that we can do is significantly alter the age of diagnosis, so instead of being aged 12, maybe that should now be aged 6. And if we do those two things, we can probably reduce half of the excess of cardiovascular deaths and adverse cardiovascular events.

Now, homozygous FH is a unique issue here. Most of these people have severely dysfunctional or absent LDL receptor function. So the drugs that we use on the left hand side that all work through the LDL receptor pathway, with statins, with for example ezetimibe, PCSK9 inhibitors, are really not effective. And we only have two options. We can either reduce the production of apo(B)-containing lipoproteins with a drug like lomitapide, but we know that's associated with an increase in liver fat. Or we can improve clearance. And thankfully now we have an option because of developments in targeting ANGPTL3, which basically improves clearance. And as a result of improving clearance, you don't get an accumulation of hepatic fat. So, even in these people with no LDL receptor function, this should be really effective. So, is it?

We have the clinical trials. These are data showing the results of intravenous injections of evinacumab in patients with homozygous FH. You can get with this injection schedule essentially approaching what accounts to about a 50% reduction in LDL cholesterol, irrespective of whether people are on apheresis, background therapy, lomitapide or PCSK9 inhibitors. The absolute reduction based on the starting levels in this study was an additional 120 milligrams per deciliter lowering. And importantly, the benefits were independent of genotype. So it didn't matter whether you were a two homozygote, a compound homozygote, or a double heterozygote. So, it was really important for these people to basically for us to be able to see that these genotypically null patients also got exactly the same benefit as all the other individuals.

So the implications really are: homozygous FH results in significant life years lost with adverse health outcomes. These start so much earlier than every other disease. Outcomes can be improved by earlier diagnosis. That means screening, detection, access and use of multiple lipid-lowering treatments that do not require LDL receptor function. And this also means that we must evaluate and accelerate the development and approvals of these new therapies in children.

Thank you for listening.