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Treatment of HoFH involving Lomitapide and Evinacumab (Part 1)


Experts discuss the effect and safety of lomitapide and evinacumab in treating patients with HoFH.

Erin Michos, MD, MHS: Lomitapide [Juxtapid] is an oral microsomal transfer protein inhibitor. It’s really responsible for trafficking triglycerides and phospholipids in the chylomicrons and the VLDL [very-low-density lipoprotein] particles during their assembly in the intestine and the liver. Trials with HoFH [homozygous familial hypercholesterolemia] have shown approximately a 50% reduction with lomitapide when added to standard therapy. It can have a pretty significant LDL [low-density lipoprotein] lowering. But the big challenge is that there can be GI [gastrointestinal] adverse effects and there can be hepatotoxicity. Lomitapide can cause serious damage to the liver and can cause elevations and transaminitis. In some of the trials, as many as 34% of patients showed elevations in their ALT [alanine transaminase] or AST [aspartate transaminase], about 3 times or more above abnormal. So significant transaminitis and the third, lomitapide can also elevate liver fats. So because of these serious potential adverse effects, it’s only available as part of this Risk Evaluation and Mitigation Strategy, REMS, program that requires regular monitoring of liver tests. Prescribers need to be enrolled in REMS so that they can be counseled on how to monitor for these side effects. And so for this reason, it’s usually, its use is restricted to lipid centers and dedicated lipid clinics, which is why upon diagnosis of HoFH; all patients with HoFH should be referred to a lipid specialist.

Eliot Brinton, MD: We need to look beyond apheresis. Apheresis in some patients is adequate, [but] in many patients it is not. Some patients can’t tolerate apheresis. It’s just not working for them. The logistics are too much. They can’t sacrifice that much out of their schedule. And the travel is too much. There is some assistance for travel which helps a lot of patients but not every patient can do apheresis. Although, in my experience, many can, maybe even the majority of the patients that are eligible can actually do it long term. What do we turn to next? I would look at lomitapide. This is a drug that we’ve had for quite a while. It was first approved in the United States 10 years ago in 2012, which is wonderful because we now have had quite a bit of experience with it in the open market, but also in clinical trials that were run before 2012. We have actually several decades with lomitapide, and that to me is reassuring.

It blocks the production of both VLDL in the liver and also chylomicrons in the intestine. Now the liver is where we want it to work because VLDL is the only source of LDL. If you can instead of trying to clear LDL through the LDL receptor, if you just are going to shut off the production of the LDL as best you can shut it down dramatically. This works very well. But there’s a potential adverse consequence in the liver, that liver fat will go up in most patients. And then there’s a potential adverse consequence in the intestine because if you block the production of chylomicrons in the intestine, you’re blocking the absorption of fat. Fat can’t be absorbed very well, so some of it gets into the intestine, causing some abdominal pain. If it’s not absorbed in the intestinal lumen very well, then it will go down and you actually can get diarrhea. You’ve got to be very careful with fat intake. It doesn’t have to be a total minimum fat intake, but you have to eat less fat intake than most people do in the west, so that is a burden on the patient. They have to do that. There’s a REMS in the US, meaning we go to the FDA, we qualify ourselves to be able to do their sort of pattern that we have to follow. Liver enzymes to look at the liver fat. So that’s the downside. The upside of lomitapide is that we’ve had it now for 20 years approved, and longer than that in terms of various studies that were done. Some registry data are very impressive in the US, and even more so in Europe, that show very good evidence for a very big drop in cardiovascular events. Roughly 3 quarters of the events seem to be prevented by this drug, which is a dramatic drop in people that are really high-risk. This data is very, very encouraging. Also encouraging is the fact that liver fat does not tend to increase over time. Initially, we all had data out to a couple of years or so, and it was going up. We were worried, is this going to continue to increase and cause liver failure? This data have not yet been presented to the FDA, so it’s not on the label for lomitapide in the US. But we have very good data now that there is definitely a plateau. None of these patients, many of whom have been on the lomitapide for 20 years or longer, have actually progressed to anything more serious in the liver so it’s a good idea to keep an eye on liver fat, and the transaminases. I’m not saying we should circumvent the REMS and the guidance in place in the label, but I am reassured that even though liver fat does go up, it doesn’t keep going up. It doesn’t seem to cause any long-term sequelae. And speaking of long-term, it does have excellent evidence to reduce a majority of cardiovascular events. I like lomitapide for those reasons, even though it is tedious. One last point about lomitapide is you have to be prepared to uptitrate. It’s kind of like the GLP-1s [glucagon-like peptide-1]. Those are now very common and very popular. But just like GLP-1s, you don’t start at the top dose first. You got to go up very gradually and let the patient adapt to it. In some ways, the ability to lower dietary fat is a plus because the patient has a way that they can control their own symptoms, which is not so much the case for GLP-1s. If you think of GLP-1s, that is really the story with the GI tract and GI symptoms for lomitapide. And the name of the game is to dose titrate the patient up or down as needed, either for GI symptoms or transaminase elevations, and then of course for efficacy. It has a top dose of 60 mg. At that dose, it will lower LDL by 50%, and even more. There are patients that have a greater response than 50%. And many patients will get close to 50%, or at 50% with well under 60 mg. You individualize your treatment greatly according to the patient’s side effects and response, and you try to go to the best possible response with either no symptoms or minimal tolerable symptoms.

Seth Baum, MD: In the management of HoFH, we use multiple medications. We do that more so than in HeFH [heterozygous familial hypercholesterolemia]. If we remember, heterozygous FH is a situation in which 1 parent is giving the mutation, or if we haven’t identified the mutation, the disease. In HoFH, it’s both parents. And what that means is the LDL receptor is damaged, either defective or null from each parent in the typical scenario where mutations are in the LDL receptor. So what that means is our medicines, our standard medicines, the statins, ezetimibe, PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, which work by upregulating LDL receptors, since there’s damage from both sides, these medications are far less effective than in HeFH. Therefore, we need to pile on more medications. Typically, also since we’re starting at a much higher LDL level than in HeFH we just do not get even close to our goal even after piling these medications on. So what we need are medications that work independently of the LDL receptor. There are 2 great possibilities available. One is called lomitapide. The other is evinacumab [Evkeeza]. Lomitapide is a microsomal triglyceride transfer protein inhibitor and basically works by not allowing the VLDL particle in the liver or the chylomicron in the gut to be developed properly. Some downside effects of this can be a fatty liver, some GI intolerance and some fat buildup in the gut. It’s an oral therapeutic and it does lower LDL significantly, by 50% or so. Evinacumab is an ANGPTL3 [angiopoietin-like protein 3] inhibitor, which also works independently of the LDL receptor. It sort of frees up endothelial lipase and lipoprotein lipase, and the endothelial lipase in particular is important here. It allows precursors, the precursors of LDL cholesterol to be taken up by the liver and degraded and therefore not created. The body doesn’t create as many LDL particles, and as a consequence LDL can fall by about 50%. That’s an IV [intravenous] infusion that’s given monthly. It’s an excellent therapeutic that was approved for adolescents and adults last year and is a very effective therapeutic. So we need to utilize more of these LDL receptor-independent therapeutics in the management of HoFH. There is 1 other therapeutic that unfortunately is not as readily available and that is lipoprotein apheresis, or LDL apheresis, which is a procedure that’s available, I think, in about 40 centers in the country. We do it in Florida at my center [Florida Atlantic University College of Medicine, Boca Raton, FL,] and it’s basically a technique whereby patients come in either every week or every other week, have blood removed from a vein in the arm, run through a filtration machine, and the LDL particles, any ApoB [apolipoprotein B] particle, frankly, is removed from the body. LDL drops 75% or so, LPL-A [lipoprotein lipase-A] also drops that amount. And the process takes about 3 hours or so.

It’s really not a terribly uncomfortable procedure. The uncomfortable part, frankly, is IV access. After that, it’s lying on a comfortable chair watching television for 3 hours. It is an interruption of life though so it would be best not to have to do this but it does very effectively lower LDL cholesterol over time and we think a lower risk of cardiovascular events as well.

Transcript edited for clarity.

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