Efficacy and Safety Data for Bempedoic Acid

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: Hello and welcome to Between the Lines, a Journal Club experience. Today’s featured article is, the “Role of Bempedoic Acid in Clinical Practice.” My name is Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center, located in Louisville, Kentucky. Joining me today is my colleague Steven E. Nissen, MD, MACC, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, in Ohio. Welcome, Steve. How are you doing?

Steven E. Nissen, MD, MACC: Thank you, Harold, I’m delighted to be with you and have thisinteresting discussion.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: Steve, I’m sure you’re the same way, for the past 20 to 30 years, we’ve been involved in all kinds of lipid-altering drug development, and ever since development of the statins we’ve always been looking for ways to alter that cholesterol production pathway. We did develop the statins, the HMG-CoA reductase inhibitors, and such, but we also worked on MTP inhibitors, ACAT inhibitors, and squalene synthase inhibitors. Now we have this drug that’s very active in development and is already approved for some indications, bempedoic acid. It’s this agent that is essentially a prodrug when it’s administered and gets activated in the liver, but not activated in the muscle. A lot of times people come up to me and ask, “What’s the clinical significance of that?” Steve, what do you think?

Steven E. Nissen, MD, MACC: I take care of a lot of these patients, and the clinical significance is pretty important. If you have a drug that is activated in the liver, the liver is where you want to inhibit this cholesterol synthesis pathway. That’s good. What you don’t want to do is have off-target effects involving other organs, and as everybody knows, many patients complain of muscle pain when you give them statins. Having in our therapeutic armamentarium a drug that doesn’t get in the skeletal muscle, doesn’t do anything in the skeletal muscle, it only works in the liver, has really important implications for patients who have difficulty with statins due to skeletal muscle symptomatology, and it’s pretty common in the literature.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: That forms the basis of a lot of the bempedoic acid development program. Yes, we do have CLEAR Harmony, a standard lipid efficacy trial, and the same thing with CLEAR Wisdom, where we’re looking at lipid efficacy and such in patients who are on statin therapy. One of the things that was done very early on is to evaluate bempedoic acid in patients with statin intolerance, and that would include the CLEAR Serenity and the CLEAR Tranquility studies. I find it very interesting that a big part of the development program for bempedoic acid was in patients with statin intolerance. Do you know of another development program where so much emphasis was placed on patients with statin intolerance?

Steven E. Nissen, MD, MACC: From the very beginning, the development of this drug was targeting them. The developers understood that the lack of penetration of the drug in the skeletal muscle was a potential advantage. They knew that this was a clinical problem that had not been well addressed. What they have done now, a variety of these studies in phase 3, have shown that bempedoic acid alone in people on statins or not on statins lowers low-density lipoprotein [LDL] cholesterol, moderately. And if you add ezetimibe, you get kind an effect that is approximately equivalent to that of a moderate intensity statin, without using a statin at all, or using a statin in very low doses. Having that data really provided the basis for guidance for clinicians on how to use bempedoic acid in their practice.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: That’s spot on. How many times have we heard the overused term “unmet need?” Here’s at least one case where that really does apply. As you said, these folks recognized early on that there truly was an unmet need for treatment of patients with a statin intolerance. We’re going to get to that in time.

Steven E. Nissen, MD, MACC: I want to talk about this issue of statin intolerance because it’s become very controversial, and I have some things I want to say about that.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: It’s a great time, go ahead.

Steven E. Nissen, MD, MACC: This disorder of statin intolerance is being assaulted from a number of different directions. People have done what they call N-of-1 [single subject] trials, and there’s a very active group that said, “There’s no such thing as statin intolerance, it doesn’t exist.” But I take care of these patients, and here’s the problem, and every clinician who sees patients like this knows this is what happens. Somebody comes into my office, and I say, “You need to be on statins.” They say, “I have tried the drugs. I have tried 3 or 4 statins, and every time I get a statin, within a few days, I get muscle pain. It’s intolerable, and I stopped the drug.” I tell them I want to try again. They look me in the eye, and they say, “I will not take another statin.” What am I going to do? It is really helpful to have a drug like bempedoic acid in our toolkit, knowing we can get LDL lowering, we can have ezetimibe and get quite a bit of LDL lowering. We don’t have yet cardiovascular outcome data, but LDL-lowering drugs have a long track record of showing cardiovascular outcome benefits. We make the assumption when we give the drugs to these people that we’re going to get a similar benefit or more to what we see with statins. It’s tremendously important that statin intolerance is in the eye of the beholder, and that’s the patient, and you’ve got to listen to the patient.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: We don’t really have time to discuss it here but looking at all the GAUSS studies that were done, GAUSS-1, GAUSS-2, GAUSS-3, and those types of things, my interpretation of those studies at the end of the day was, yes, there are some patients where it’s difficult to objectively determine if they have statin intolerance. But I also believe those studies, particularly GAUSS-3, did suggest there are some patients who truly have statin intolerance. At the end of the day, as you said, the statin intolerance definition is whatever the patient tells you it is.

Steven E. Nissen, MD, MACC: Yes, it is.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: Here we have these clinical trials, and the efficacy trials get around 18% LDL cholesterol lowering, but look at these studies over here, the CLEAR Serenity and CLEAR Tranquility. These are patients maybe with a little higher baseline LDL cholesterol, but these are patients who were, at best, on a very low-dose statin, yet look at their LDL cholesterol lowering with bempedoic acid—in the 20s [mg/dL]. What do you make of that? What do you make of what appears to be a difference in efficacy, when you compare patients who are not on statins versus patients who are on statins?

Steven E. Nissen, MD, MACC: There appears to be some interaction here. We sometimes use bempedoic acid for patients who are on full doses of statins, where we really need more LDL reduction, and that’s a perfectly appropriate thing to do. We might even add bempedoic acid and ezetimibe to try to get more efficacy. But the sweet spot here is in the patients who can’t tolerate much statin. Maybe they’re taking some rosuvastatin twice a week, and that’s not good enough and we need more. Their LDL cholesterol, as you can see here in CLEAR Tranquility, is 130 [mg/dL] or so, and that is, for a secondary prevention patient, that’s just not acceptable. You get 28%, 30% [cholesterol lowering] even, sometimes in some patients. You can see the 95% confidence intervals range from 22 and a half to 34, very strong efficacy. I would like to point out here another aspect of this drug that is interesting and may play out in the CLEAR Outcomes trial, and that is the drug has a strong anti-inflammatory effect. Hs-CRP [high-sensitivity C-reactive protein] goes down a lot, perhaps more than we see with comparable degrees of LDL reduction from statins. A number of us believe that CRP reduction is important. Paul M. Ridker, MD, MPH, and I both published manuscripts in the New England Journal of Medicine as far back as 2005 that showed evidence that some of the statin benefit came from the anti-inflammatory effects of the drug. I’m intrigued by the fact that bempedoic acid does have a very strong anti-inflammatory effect.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: That’s all very interesting. That’s the efficacy side. Here on the safety side, it looks pretty good with regard to the liver, creatinine. If you had to focus on the things most clinicians, when they read the prescribing information, they zero in on gout and tendon rupture. We did an analysis of the gout issue, and it should come as no surprise that the people most likely to get gout are those who already had a history of gout, and who had high uric acid levels. If they didn’t have gout and their uric acid levels were normal, then they approximated in the placebo group with regard to the incidence of gout. But then there’s this very curious thing about tendon rupture, what do you make of that?

Steven E. Nissen, MD, MACC: I disagreed with the FDA on putting this into the label. I thought the data on tendon rupture were very weak. I’m not sure it’s going to be confirmed in the very large CLEAR Outcomes cardiovascular trial, but it’s in the label. If it’s in the label, it’s prudent for physicians to pay attention to it. Now, keep in mind, that fluroquinolones can produce tendon rupture on their own. I would be careful about adding bempedoic acid for these patients on corticosteroids or fluoroquinolones, but I’m not sure it’s going to turn out to be a real effect. It certainly is not a very common effect. The gout issue is more significant, and we have seen some patients with gout. I have given bempedoic acid to some patients with gout when I thought the benefits exceeded the risks, particularly if they were having their uric acid treated with allopurinol. If they’re really well controlled, as long as you’re careful, you can use bempedoic acid in these patients, but you have to be aware there’s a potential risk. If I had to trade an attack of gout for a myocardial infarction or a stroke, the reduction of myocardial infarction and stroke is what we expect to see from this drug, then I might accept the fact that I would occasionally have an episode of gout in patients.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: As I said before, the risk of gout, as you might expect, does go down with the lower uric acid levels. That speaks to exactly what you said, you’ve got to know about it, you’ve got to treat it, and you’ve got to try to prevent it. Then there are also some restrictions on the particular doses of simvastatin and pravastatin, but other than that, one of the positives of bempedoic acid is that it does seem, at least thus far, to have a pretty reasonable safety profile. Would you agree with that?

Steven E. Nissen, MD, MACC: Absolutely. I’m not concerned about safety. I’m aware of these issues that have popped up, and they’re in the label, and you want to consider the FDA-approved label whenever you give a drug. The issue of pregnancy has not been well studied or the problem of breast feeding. These are all very reasonable things to put in a label, and it’s not really been studied in those patients.One has to be careful with a history of gout, and I would be very careful about giving bempedoic acid to somebody on a fluoroquinolone. Most people getting fluoroquinolones are getting them for a short course of treatment, for say, a urinary tract infection. These are not drugs that are given chronically. We’ll see if the tendon rupture problem is actually observed in the very large CLEAR Outcomes trial, but for now, this is really an easy-to-give drug with a good safety record.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: In summary, we have this newer agent that has been approved for some time. One of the nice things is it works through impairment of some of the enzymes in the cholesterol synthesis pathway, and that’s a mechanism we’ve all come to know, and we’re comfortable with that. It lowers LDL cholesterol pretty reasonably as monotherapy, and as you mentioned, you can get, say, 38% LDL cholesterol lowering if you administer it with ezetimibe. That approximates the LDL cholesterol lowering by a moderate intensity statin. We have an outcomes study we’re going to be talking about, where we’re going to be able to see the impact on cardiovascular disease, and with regard to safety, it’s mainly focused on gout and possibly, tendon rupture. We’re going to get more information about that with longer-term studies. Do you have any additional things to close this section?

Steven E. Nissen, MD, MACC: I don’t. I’ve used the drug in quite a number of patients, and I find it to be something that’s very well tolerated.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: Thank you very much.

Transcript edited for clarity.