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Homozygous Familial Hypercholesterolemia (HoFH)
Video

Effective and Emerging Treatments for Lowering LDL-C in HoFH

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Eliot Brinton, MD, president of the Utah Lipid Center in Salt Lake City, discusses appropriate treatments for homozygous familial hypercholesterolemia (HoFH).

Hear Dr. Brinton talk about genetic testing and patient counseling.

Question:

From your experience, what therapeutic approaches have proven most effective in lowering LDL cholesterol levels in individuals with homozygous familial hypercholesterolemia?

Eliot Brinton, MD:

What about these non-LDL receptor-based treatments? To me, the first one of these is going to be lipoprotein apheresis. It’s not used very widely. There are a relatively small number of centers around the U.S. and even around the world. It’s rather expensive compared to [other] medications, and it’s a little bit cumbersome. The patient has to sit in a chair for 3 hours or so and the blood circulates through the machine and through these columns that take out the LDL. It’s difficult, but it’s very, very effective, and it does not have anything to do with the LDL receptor. It will lower LDL levels by 60%, 70%, 80%, 90% in a single sitting. The LDL levels come back up rather quickly. But for that reason, we tend to do this every 2 weeks. Even a little bit more often if the patient’s more severe, but on average of every 2 weeks. That’s a lot of trips back and forth to the apheresis center.

But insurance will virtually always cover this. The amount of out-of-pocket expense to the patient is minor to 0, and we never go ahead and do apheresis unless we have that insurance available. It is just so incredibly effective in terms of LDL lowering that we just really appreciate this treatment greatly. One very important thing, in fact, the most important thing about lipoprotein apheresis, is its efficacy in reducing cardiovascular events. The data that we have from many countries is really dramatic. We’re talking about at bare minimum a 60% event reduction. Many studies showing 70%, 80%, possibly even a little bit better than 80% event reduction. This is very dramatic for 2 reasons. First of all, even in the best of circumstances, those standard 4 LDL receptor-dependent medications that we have talked about are giving us event reductions in the neighborhood of 15%, 20%, 30%, maybe 40% at maximum event reduction, whereas lipoprotein apheresis is way more effective.

It’s very difficult, it’s expensive, but insurance will cover it and it can be done, and it’s a lifesaving treatment for the more severe cases. A patient with preexisting cardiovascular disease, prior heart attack, ongoing angina, having had several stents or bypass grafts or disabling strokes, this can be extremely helpful, and it’s well worth doing. I would urge the listener to always consider this. Almost always in the U.S., you’re within driving distance of an apheresis center. The FH Foundation website is a great place to go to look up these lipoprotein apheresis centers and refer the patient to that for evaluation because this is definitely our best treatment for event reduction. Although it’s cumbersome and difficult, it is so amazing for so many patients, and those patients that are on lipoprotein apheresis are generally very, very positive about it.

Now, as a next treatment, we have 2 classes of drugs that are independent of the LDL receptor, and first one of these to come out was an MTP inhibitor, basically blocks the formation of an apolipoprotein (apo) B-containing particle. This happens in the liver. The liver is making VLDL. VLDL, as you know, is the source of LDL. If we can cut off LDL at its source, then the clearance is less of an issue, and that is how this medication called lomitapide works. By blocking the formation of VLDL, it does tend to cause fatty liver, so triglycerides accumulate in the liver. The question is, is that safe? The answer is there are safety concerns. In fact, there’s a REMS, the FDA requires a little advanced training and certification on the part of the provider who will prescribe lomitapide because we have to know about fatty liver and check for it. The good news is that the longer-term data that we now have from lomitapide suggests that this is not progressive and not harmful in terms of progression to cirrhosis.

But the REMS is still in place; we don’t have quite enough long-term data to have proven this adequately. The other concern is that this drug, lomitapide, blocks the formation of a chylomicron in the intestines. The intestine is going to absorb dietary fat. It will try to make a chylomicron, but it can’t, so the intestinal cells and the intestinal wall fills up with triglyceride. Now that causes abdominal pain. It causes problems, and the best way around that is to reduce dietary fat, so just plain triglyceride in the diet, dietary fat. Reducing that helps the patient tolerate lomitapide. Of course, triglyceride intake doesn’t have anything to do with cholesterol or atherosclerosis per se, but that’s a requirement for use of lomtapide.

It’s a very, very expensive drug. It’s only for homozygous FH patients. It’s only those patients who have tried and failed the 4 LDL receptor classes of drugs. Then it also, I would say lipoprotein apheresis, and it can be added to lipoprotein apheresis. If the patient’s responding, but not with enough response lomitapide can readily be added. But it does have those caveats and those difficulties. Paradoxically, even though it’s a very expensive drug, my experience is that the payer will almost always readily approve it because they know that it’s a very, very rare patient, a few per million in the population who might qualify for lomitapide. The other much newer drug is a drug that acts by inhibiting something called ANGPTL3. ANGPTL3 is a factor that blocks the action of lipoprotein lipase and endothelial lipase. Now, we haven’t traditionally thought that either one of those have anything to do with FH.

They’re not on the list of mutations that can cause FH, so how does this work? Giving people an antibody to ANGPTL3 will block the blockade. It’ll block the inhibition, meaning increasing the activity of lipoprotein lipase. You say, “Well, that could be a treatment for high triglycerides,” and it might be, but in fact we haven’t used this method to treat triglycerides yet. But also, it increases the activity of endothelial lipase. Somehow the combination of those 2 allows the body to process LDL in a way that is independent of the LDL receptor with the severe lack of LDL receptor activity that we see in the patients that have very difficult to manage homozygous FH. That’s the patients that start out with an LDL well above 500. Those patients then will respond to this medication. It’s a monoclonal antibody. It’s given once a month by intravenous infusion, and it really works very nicely.

There’s no dietary restriction whatsoever, and it’s fairly good in terms of the side effects. It doesn’t have a REMS, so it’s in many ways easier to use. Lomitapide, I should add, is a pill. So taking a pill once a day is easy, but the dietary restriction and the need for liver testing as part of the REMS make it a little more awkward. This drug is called evinacumab. It’s the antibody that blocks ANGPTL3 that then un-inhibits LDL and endothelial lipase. These 2 medications, the oral lomitapide, the MTP inhibitor, and the ANGPTL3 inhibitor, the evinacumab infusion, are both indicated only for homozygous FH. Interestingly, they both work to roughly the same degree. They both will give a roughly 50% LDL lowering, which doesn’t sound like much. But remember that all these other medications that’ll routinely give 50% to 60% LDL lowering in the case of the statins and the PCSK9s rarely give anywhere near even half as much in these more severe patients.

Let’s say you get a 5% or 10% lowering with a statin and another 5% or 10% lowering with the PCSK9 inhibitor and you start out at 700, obviously you’re in huge trouble, and you probably are going to need either one or in many cases both of these 2 medications that will lower LDL levels by another 50%. I would say again, on top of lipoprotein apheresis is that, again, will lower it even a little bit more. With all 3 of those, which we don’t use hardly ever, the triple therapy of these 3 very expensive and very difficult treatments, in fact, is often what is needed in the most severe cases. We do our best with the 4. We go on to the medications or the treatments that are more specific for the more severe cases, lipoprotein apheresis, lomitapide, and/or evinacumab, and we use 1 or more of these 3 to treat the patient.

The goal for a young patient who’s never had an event is in the neighborhood of an LDLS than 130 or 100 for a patient who’s had a prior cardiovascular event, and also for an adult patient, the goal is actually less than 55. We try to get the LDL very, very low. To reach those goals, we often will have to use at least 1 if not 2 or 3 of these more advanced treatments. Again, the payer is usually quite willing to pay for these extremely expensive treatments because it’s so rare that we actually need to use them. Lots of challenges in treatment, but we have several tools that I think if we can do this sequentially we’re in good shape. Then back to the question of diagnosis. Does this patient have homozygous FH? We can look at this genetically, but I don’t usually do that.

I look at it phenotypically and that is I treat with the 4 agents. Do I get them to go? If I do, great. If I don’t, then I go on to apheresis or lomitapide or evinacumab in whatever order, and I will use those as I need to. Does it matter if I’ve genotyped a patient homozygous FH? No, the FDA does not require genotyping. I will just generally treat in sequence and then I discover, “Oh, this patient is a homozygous FH patient because, in fact, they did not respond adequately to those 4.” Sometimes they will to the fourth, the PCSK9 inhibitor, be a genotypic HoFH patient. But again, I don’t need to know that because I’m just going to use those 4 treatments anyway. We have pharmacologic, we have non-pharmacologic treatments, and we’ve got pretty good armamentarium at the moment.

Question:

Could you provide an overview of any emerging therapies or treatment modalities that demonstrate promise in the management of homozygous familial hypercholesterolemia?

Eliot Brinton, MD:

We’ve talked about the existing approved treatments, and these are wonderful. The 4 that are LDL receptor-dependent, we can get some benefit. We always try these, even if we’re convinced from the beginning that the patient’s HoFH, we have the 3 non-receptor-dependent treatments. These are the ones that work so nicely in the patients with the highest baseline LDL and with little or no residual LDL receptor activity with which we can work by upregulating it. But we then have 2 approaches in terms of emerging treatments. First, let me mention PCSK9. PCSK9 inhibitors are indicated. They’re effective and are indicated for homozygous FH, and they’re only for the milder cases. Those would be the antibodies, evinacumab and alirocumab, and then inclisiran, the siRNA. Those work, but only to a minor degree and only in the patients that have milder FH anyway.

There are new developments in the PCSK9 field. There’s an oral PCSK9 inhibitor that’s being developed by Merck. It’s an MK-0616. There’s something called lerodalcibep, which is LIB003 being developed by LIB therapeutics. It is something that is not a monoclonal antibody but works like a monoclonal antibody to block a PCSK9. These will have some role, but my prediction is that they will have a role that is similar to what we already have with the PCSK9 inhibitors, which you remember were the fourth and final LDL receptor-dependent arm of our treatment for homozygous FH.

What about things that are independent of the LDL receptor? Here we have some very nice developments in the area of ANGPTL3. We already have an evinacumab, which is a monoclonal antibody that blocks ANGPTL3. We have 2 siRNA products that are in development, and these are zodasiran, which is developed by Arrowhead, and solbinsiran, developed by Eli Lilly. These are going to be, I think, complimentary, probably relatively similar to our monoclonal antibody evinacumab, but we’ll have to see. They’re using a different platform, siRNA, instead of monoclonal antibody. We’re never sure, especially this early on in the process of developing these new platforms of drugs, exactly how they’ll turn out. But we’re eager to get additional treatment options, especially those that are independent of the LDL receptor because we have a large unmet need because these patients have such very, very high levels and they need so much lowering and we can get little, if any, mileage out of upregulating the LDL receptor.

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