A discussion on how to approach the real-world application of bempedoic acid with the Chief of Cardiology at Baylor College of Medicine.
With approval as an adjunct to maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease, bempedoic acid has the potential to transform treatment algorithms.
Backed by the phase 3 CLEAR program, which included 4 trials used in support of bempedoic acid’s approval, the therapy sports an undeniably strong clinical profile—indicating treatment could result in reductions of LDL-C as high as 18%. The first-in-class therapy was also at the center of an analysis presented at AHA 2019 that found could also help improve on-HDL-C, total cholesterol, apolipoprotein B, and hsCRP from 12 weeks of treatment.
However, as with every approval, the prescribing practices in a real-world setting may be different from those in a clinical trial. Creating questions that may go unanswered by labeling information.
With this in mind, HCPLive® reached out to Christie Ballantyne, MD, chief of Cardiology at Baylor College of Medicine and chair of the steering committee for bempedoic acid, to take part in a special FDA approval edition of the DocTalk Podcast and discuss how to effectively prescribe bempedoic acid in a real-world setting.
Editor's note: This podcast was recorded before the FDA announced the approval of bempedoic acid and ezetimibe and, as such, is not discussed in the context of use in a clinical setting in this recording.
HCPLive: Hello, and welcome to this special FDA approval edition of the DocTalk Podcast. I'm Patrick Campbell, editor with HCPLive, and I'll be your host for today's edition of the show. Today we'll be talking with Dr. Ballantyne about the approval of bempedoic acid and where this drug fits into current regimens.
First, I just like to start with you introducing yourself Dr. Ballantyne and then we can dive into some questions.
Ballantyne: Hi, I'm Christie Ballantyne. I'm the Chief of Cardiology at Baylor College of Medicine in Houston, Texas. And I was the chair of the phase 3 lipid advisors for the bempedoic acid program.
HCPLive: Now, since bempedoic acid has been approved, I guess the first question is: how monumental is it that for the first time in decades, we have a non-statin option approved for lowering LDL-C, even as an adjunct?
Ballantyne: Well, I think it's an important new option for both physicians and patients. Statins are fantastic drugs. They're highly effective. We have great data on them. But if we look at the 2 most common reasons people are seeing doctors or nurses or healthcare providers is basically high blood pressure and cholesterol.
Now, if we look at the way we treat blood pressure—we have lots of options. The average patient is pretty frequently on combination therapy. That's an older feel, but you know, we have many, many different options and different mechanisms of actions. So, you can work through and get people to their goals.
It's interesting if we take a look at the field of cholesterol, usually, people stop after option number 1. So, a lot of people are not being effectively treated. I think this is an important step to be able to offer our patients new options to help them get their LDL cholesterol is down to a zone that's more favorable.
HCPLive: Thank you for that. And, next, what does the ideal patient population for bempedoic acid look like? As with every drug, not every person that has the conditions it was approved for will see the same benefit that other people might.
So, what does the ideal patient or bempedoic acid look like?
Ballantyne: So, the first thing is that this is not going to replace statins as first-line therapy. Statins will remain the first-line therapy.
So, where this is used is if you have a high-risk patient and on maximally tolerated status, and they're still not where you want their LDL cholesterol to be. The approval specifically focuses on people who have documented atherosclerotic cardiovascular disease or people with familial hypercholesterolemia. That's a group that we know it's sometimes challenging to get their LDL cholesterol down to a desirable range.
And maximally tolerated statin varies from patient to patient. If a patient is able to tolerate a high dose of a high efficacy statin. Then very frequently, we don't need to add a second medication, but it happens that there are people who cannot tolerate these dosages or else they just have very, very high LDL or don't respond well and they need additional therapies.
HCPLive: Thank you for that. And as you touched on bempedoic acid was approved as an adjunct for lowering LDL-C. But some analyses of the 4 CLEAR trials found benefits and other areas as well, including HDL cholesterol, total cholesterol, and hsCRP. Can you dive a bit into the mechanism of ACL inhibitors and explain what this might mean in a clinical setting?
Ballantyne: Right, so this drug inhibits ATP citrate lyase, and that's an enzyme that's important in the synthesis of cholesterol. It's a prodrug, it gets activated in the liver to the active form. So, specifically targeting liver production of cholesterol.
That's a similar mechanism to what statins do —they're also inhibiting cholesterol synthesis. It's a different enzyme HMG-coareductase, but they both end up lowering cholesterol in a cell and increasing LDL receptors. This is complementary to the mechanism of action, for example of ezetimibe that blocks cholesterol production or PCSK9 inhibitors.
So, what ends up happening is and what we're seeing from the CLEAR program is that the drugs—could be various options—combinations added together, and you reduced LDL cholesterol and that means you're going to also reduce total cholesterol.
What was interesting is the reduction in C-reactive protein. statins, which block cholesterol synthesis, reduce CRP and so does this agent. Some of the other therapies that work by different mechanisms PCSK9 inhibitors alone do not lower CRP, ezetimibe alone does not lower CRP. So, it seems to be something that's shared with the way a statin works.
HCPLive: Thanks for diving into that a bit deeper for us. And now from a patient perspective—1 of the if not the biggest question for any drug in this field—can we expect the effects to translate to a reduction in mortality and or serious events for patients? Is this lipid-lowering effect going to translate into something like that you think or is it too early to tell?
Ballantyne: Well, in regard to this question, I think 1 of the reasons that the FDA approved this for the use of LDL lowering therapy is that levels of LDL cholesterol are a very strong surrogate marker for benefit. In other words, the FDA would approve drugs to lower LDL or that lower blood pressure and particularly if they understand the mechanism. The mechanism here is by basically upgrading LDL receptors, which is the same way that statins work, PCSK9 inhibitors, ezetimibe all work that way. They all do the same thing and they've all shown benefit.
So, we don't have outcomes trials yet, but we do have a considerable amount of data. Also, it's very important that there is a large outcomes trial in patients who are statin-intolerant that is already fully enrolled. So, we'll have that answer pretty soon, but I think we have sufficient data that someone can end up sitting, if I need further LDL reduction I have an agent, which has been studied in a lot of patients, it's shown that it's effective. It has a good safety profile and I have further data in the near future.
HCPLive: Thank you for that, and now just lastly, really quick, is there anything else that you think is important that clinicians should keep in mind when prescribing bempedoic acid to a patient in the real-world setting? I know we saw an increase in rates of hyperuricemia and tendon rupture in the studies. How do you approach that in a clinical setting?
Ballantyne: So, 1 thing that's important. The first question is asking someone do they have a history of gout. People who had a history of gout in higher level of uric acid, those were the individuals who are most likely to have an increase in uric acid in they would also have an increased risk for gout.
That's important. Does someone have a history of gout and what is the level of uric acid. If they're taking allopurinol and the level is low, then you're fine. Then there are other individuals that may be at a high risk. So, it would not be unreasonable if you were concerned about someone getting a baseline level of uric acid. If it's high, you keep an eye on that.
The issue of tendon rupture—that this is 1 that I think we're going to need more data on. As we were doing the trials, it really wasn't very clear and 1 of the things that there was a 2:1 randomization. So, we had twice as many patients on the treatment as the placebo but obviously it's a warning. So, if someone is starting to have problems with a tendon and they're having some soreness or pain, it would be reasonable to stop the medication and then to follow the patient and see if things improved or not.
HCPLive: Okay, that was about it on my questions. Is there anything else you wanted to add about bempedoic acid?
Ballantyne: Just 1 comment here. I think that bempedoic acid is a new option, but I think 1 of the things that's going to be happening is that in general, we will begin to treat lipids in a manner that's probably more similar to the way that we treat blood pressure. And with blood pressure we'd start with monotherapy, we quickly go to combination therapy—frequently have 2 medicines in 1 pill—and it's very common to actually have people who are on 3 medications in a high risk person where you're trying to blood pressure down to a low level.
That's going to be probably similar, I think to the future for a lot of people who are having difficult to treat LDL that we're going to use more combination therapy.
HCPLive: All right, well, I just want to say before I let you go, thank you for taking part in the DocTalk Podcast, Dr. Ballantyne.
Ballantyne: Thank you.
HCPLive: Alright, that's it for this edition of the DocTalk Podcast. I'm Patrick Campbell, editor with HCPLive. Thank you for listening.