Understanding the Pathophysiology of HoFH Informs Treatment Options

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Seth J. Baum, MD, Chief Medical Officer of Flourish Research and the Vice Chair of the Board of the Family Heart Foundation, discusses the 2 treatment options for homozygous familial hypercholesterolemia (HoFH): evinacumab and lomitapide.

Question:

Could you explain the pathophysiology of HoFH and how it leads to such severe elevation of LDL cholesterol?

Seth J. Baum, MD:

The pathophysiology is interesting and very important from the standpoint of finding a good therapy. The common denominator with all of these mutations that I’ve mentioned, LDL receptor, ApoB, PCSK9, is that the LDL receptors function poorly or not at all. There can be null mutations or negative receptor, negative mutations where the receptor has about 0% to 2% functionality. Then there’s the other kind of mutation, which is not as extreme, and it’s a defective LDL receptor we say, and that’s between 2% and 25% functionality.

Then you have to say the LDL receptor is not working at all or not well, and what does that do? The LDL receptor is an enormous number of LDL receptors in hepatocytes that will bind to an LDL particle and bring it internally into a hepatocyte for degradation. If the LDL receptor is not functioning well, LDL just accumulates in the blood at extraordinary levels. Typically, the worse the mutation, the higher the LDL.

The pathophysiology influences our therapeutics, because most of our drugs for LDL reduction rely on the LDL receptor to work, so they upregulate LDL receptors. If your LDL receptor is non-functional or poorly functional, you get much less bang for the buck with each of these therapeutics, so statins, Ezetimibe, PCSK9 inhibitors, all upregulate LDL receptors. They’re much, much less effective in a patient with homozygous FH and sometimes in patients with 2 known mutations, really not effective at all, so we need other therapeutics to effectively treat homozygous FH.

We have LDL apheresis or lipoprotein apheresis available, but there are only 70-some odd sites in the country that do this, and it’s every week or every other week having your blood cleansed with 2 large IVs and taking 4 hours or so. We do that in Florida where I am; we have a center that does that and it’s very, very effective, but not a first choice if you can avoid it, right?

That’s available, and then there are a couple of other drugs. There’s lomitapide, which is an MTP inhibitor, and then there’s evinacumab, which is an ANGPTL3 inhibitor. Those 2 drugs are available only for HoFH, homozygous FH. You can’t use them in heterozygous FH; you can’t use them in other lipid abnormalities.

Lomitapide has been around longer than evinacumab. Lomitapide reduces LDL 40% or so and works independently of the LDL receptor. The problem is you can get a fatty liver or you can get significant diarrhea, you can get elevated liver tests, so there are certain constraints in using lomitapide. It still is used though and still has a place.

Evinacumab, the ANGPTL3 inhibitor, is not an oral drug like lomitapide, but it’s an infusion that’s given every 4 weeks. It requires either an infusion center or we do it at the apheresis center, but it can be done at home as well, but you need an infusion nurse typically to administer it.

It’s a very well-tolerated drug. As all drugs, there are potential side effects: flu-like syndrome or risk of systemic hypersensitivity reactions, even anaphylaxis. It comes with risks, but it is generally very well-tolerated and reduces LDL 50%, that’s in children 5 through 17, and adults all around 50% reduction of LDL, and that’s on top of whatever else patients are taking. Very effective medication and in my experience well-tolerated.

Those 2 drugs are both LDL receptor-independent drugs, and therefore have much greater efficacy than our other therapeutics that I just mentioned.