Lomitapide and Evinacumab for Treatment of HoFH: Part 2

Evinacumab is highlighted as a new therapy for treating patients with homozygous FH.

Eliot Brinton, MD: There has been a recent breakthrough in HoFH [homozygous familial hypercholesterolemia] treatment, and that is the approval of a second medication back in February 2021 for something called evinacumab [Evkeeza]. It’s a monoclonal antibody given by intravenous infusion, and it’s very effective. But let me start first with the backstory. It’s really fascinating. This drug works in a way that most of us would not have anticipated it would work in HoFH. It doesn’t work at all with the LDL [low-density lipoprotein] receptor, which is fine. It works by disinhibiting lipoprotein lipase and endothelial lipase by blocking something called ANGPTL3 [angiopoietin-like protein 3]. ANGPTL3 is a fairly recently discovered factor that is made by the body. ANGPTL3 blocks LPL and blocks endothelial lipase. And the evinacumab disinhibits that. What does LPL do? Lipoprotein lipase is responsible for triglyceride metabolism primarily. And we want to have more lipoprotein lipase activity to reduce severe hypertriglyceridemia. But that is not the story behind evinacumab. The story behind evinacumab is that for whatever reason that is still not completely understood, facilitating endothelial lipase helps remove VLDL [very-low-density lipoprotein]. And apparently, before it can become LDL, and maybe even after it becomes LDL. It’s like lomitapide [Juxtapid] in the sense that you’re reducing the input of LDL into the system, but you’re doing it in a totally different way. You’re not blocking the assembly of the LDL, or for that matter, chylomicrons. You are actually facilitating their removal before they can become LDL. And that’s very interesting, and surprisingly very, very effective. Its efficacy in its pivotal clinical trial was 50%, exactly the same as the average efficacy of lomitapide. But here you don’t have to worry about dose up-titration. It’s just 1 dose. You don’t have to worry about dietary intake, because as best we can tell, it has very little or no effect on the intestine, and it has no ability to block the formation of chylomicrons or block fat absorption. It also does not cause fat accumulation in the liver, as best we can tell. The 2 burdens that we have with lomitapide are gone with evinacumab. The side effects are relatively few. If you look at the label, there is mention of an allergic reaction. And in rare cases, that can be severe, so you need to keep an eye on that especially early on in the treatment. But it is a remarkably clean drug in terms of any drug reactions or adverse effects. It’s just really very, very nice in that regard. It’s given by intravenous infusion that takes an hour. It’s done once an hour. It’s really quite convenient. Can be done in the patient’s home if they wish. Travel logistics are really pretty much eliminated. You can do it in an infusion center; you can do it in your own clinic if you want to. We tend to do it in our patients who are already on apheresis, and we do it as part of their apheresis. We’ve already got a needle in their arm, so we can just easily give the intravenous infusion. And there are some data both with evinacumab and also with lomitapide, that you can reduce the dependency on apheresis. And for many patients, that’s a big deal. You can do it less often; you can even stop apheresis if that’s what the patient wants to do. The good news also is that there’s no contraindication or even concern about drug reaction by using evinacumab with lomitapide. That’s great news because again the more severe cases, your LDL is staying the 600 to 700 range after you’ve gone through all 4 of the standard LDL receptor-related treatments.

An important thing as these patients are so severe, some of them are nowhere near the goal of less than 70. I really want to get the patient as far under 70 as I can so I will often use all 3 of these advanced treatments on the same patient. I may have them on a statin; there may be some pleiotropic effects with or without much evidence for LDL-lowering. The other medications I’m a little less likely to use, although I will sometimes continue the use of the PCSK9 [proprotein convertase subtilisin/kexin type 9] antibodies, or the snRNA [small nuclear RNA] if LPL-A [lipoprotein lipase-a] is elevated. LPL-A can be elevated in a patient with homozygous FH, but not often. But if it is, then that’s a reason that I would continue the PCSK9 inhibitors, even if there’s little or no LDL effect. But other than that, I’m using 1 or 2 of the basic treatments for LDL. I will often end up using 2 or 3 of these 3 specialty treatments. And the reason is we know the LDL control. And you can mix and match according to the patient’s circumstances but realize that there’s no contraindication to using both evanicumab and lomitapide together. There’s actually no problem with using either one of those with apheresis. Any 1 or 2 of those 3, or all 3 together, you are driven by the patient’s LDL level on treatment. And you really want to get it down as low as you can, so be prepared to use as many of those treatments as you need. You can drop one of the treatments, or reduce the dose of one of the treatments. At least the lomitapide, you can reduce the dose. If you wish to customize the treatment to the patient, of course, that’s always a good idea. But with these patients, you’re going to customize, and you do your best to get the LDL below 70 as much as possible. It’s kind of fun to have these challenging patients but we’re very fortunate to have 3 excellent treatments that are totally independent of the LDL receptor, and that’s a huge deal. One little aside to just mention…If a patient is going to use lomitapide, they really should be on no alcohol at all because the alcohol of course will tend to raise liver fat and irritate the liver. That’s 1 other thing that is a part of the lomitapide story and again may shape your position on using lomitapide vs evanicumab. There’s really nothing about evanicumab that is really harming the liver, or in any way interacting with alcohol. Although, of course, we might want to have them reduce alcohol for other reasons, but that’s really not a player for that and it’s not a player for apheresis.

Erin Michos, MD, MHS: Evinacumab is FDA-approved as an adjunct to other LDL-lowering therapies for the treatment of patients aged 12 years and older who have HoFH, and it received FDA approval in February 2021. As I alluded to, it’s currently undergoing priority review by the FDA for evaluation of its use in children aged 5 to 11, so hopefully, we’ll hear about the younger pediatric age in March 2023. So how does this work? Evinacumab is a fully human monoclonal antibody targeting ANGPTL3. ANGPTL3 is a protein that inhibits lipoprotein lipase and endothelial lipase. Importantly, the mechanism of this drug, the reductions in lipid-lowering therapy by inhibiting ANGPTL3 is independent of the LDL receptor. And that’s why it has this advantage in HoFH because all those other therapies we were talking about—statins, ezetimibe, PCSK9 inhibitors, and glycerin—all really depend on the up-regulation of the LDL receptor. And this works independently of that. There was a large trial called the ECLIPSE trial and evaluating specifically patients with HoFH and compared to a placebo, giving evinacumab monthly reduced LDL by about 49% from baseline. Some of the issues are the cost point that it was priced at, and that can sometimes be challenging in terms of getting prior authorizations. It’s also given by an IV infusion, dosed about 15 mg/kg by IV infusion that you give over 60 minutes every 4 weeks, so it does involve patients coming into a center that can give an IV infusion and patients don’t give it to themselves as they would do with the PCSK9 monoclonal antibody of subcutaneous injections.

Transcript edited for clarity.

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