Esperion Therapeutics, Inc. (ESPR) Earnings Call Transcript & Summary

Good day, everyone. My name is Leila, and I will be your conference operator today. At this time, I would like to welcome you to Esperion's key opinion leader Investor event, Breaking the Statin Intolerance Barrier, Closing the Care Gap in Cardiovascular Health. [Operator Instructions] At this time, I would like to turn the call over to Sheldon Koenig, President and CEO for Esperion.

Thank you so much. Good afternoon, everyone, and thank you for joining us for this most important segment on Statin Intolerance Barrier, Closing the Care Gap in Cardiovascular Health. If we can go to the next slide, please. So our forward-looking statement and disclosures. I won't read it, but it will be available on our IR site. Next slide. So this is our agenda today. First of all, I just want to thank our speakers who have joined us today, Dr. Fatima Rodriguez, who -- all of our speakers will be introducing themselves in the later half of this session. Dr. Dharmesh Patel; and LeAnne Bloedon, our Vice President, Head of Development, who will also be giving a presentation post my remarks. Our agenda today, opening and introduction. The next segment will be when treatment becomes a barrier, empowering patients to stay on therapy and then a question-and-answer session with both Dr. Fatima Rodriguez and Dr. Dharmesh Patel. And again, we thank them for joining us today for this most important segment. Next slide. So just a quick coverage of recently, as you know, Esperion Therapeutics, we held our Q3 earnings and again, delivered consistently on strong execution. The third quarter was a strong quarter for us. As a matter of fact, the third quarter was one of the strongest third quarters we actually have ever posted in the company's history. Our Q3 total revenue was $87.3 million, which represented close to a 70% year-on-year growth. And our Q3 U.S. net product sales was $40.7 million, which represents a 31% year-on-year growth. As many of you know, we finalized agreements with four generic manufacturers. One of the largest ones, Dr. Reddy actually settled with us in the third quarter. And as you know, the settlements now take us to the year 2040. And as we mentioned in our prepared remarks in the third quarter, we'll actually be talking about our 2040 vision later in the year and going into next year. We showed a 9% increase quarter-over-quarter in retail prescription equivalents. And something that was also very exciting is at the ESC meeting this year, bempedoic acid received a Level 1A recommendation in updated ESC/EAS guidelines for management of dyslipidemia. LeAnne will go into some greater comments regarding that. Next slide. So just to give you an idea as it relates to statin intolerance and what we are doing as it relates to performance and some of the initiatives that we're taking. Currently, the NEXLETOL and NEXLIZET franchise are outpacing the broader lipid-lowering market. We're delivering growth that has exceeded all other non-statin therapies, including branded competitors. Just as it relates to leadership expansion, we recently announced that John Harlow will be joining us as our Chief Commercial Officer, and many of you will get to meet him at the Jefferies Conference, which begins on November 17. We've actually conducted our own market research to really look at the market opportunity. And it's really interesting to note that approximately 50% of patients who begin statin therapy, either discontinue treatment or had over a 6-month gap in therapy within 2 years, representing a significant opportunity for NEXLETOL and NEXLIZET. We talk all the time how cardiovascular disease is the #1 killer in the country in the world. This is just another fact of how patients are unable or unwilling to take therapy as it relates to statins today. Brand momentum, we launched our new tagline campaign, can't take a statin, make NEXLIZET happen, targeting statin-intolerant patients. And I would also say that quantitative data has shown that healthcare professionals were really showing gains in awareness and the use of NEXLETOL and NEXLIZET. This is primarily due to not only the clinical profile of our products, but also the ease in getting our products with the access we have both commercially and in Medicare. Our commercial performance, we had a 9% increase, as I said, in our total RPEs. We had a 7% increase in total number of prescribers. Our total prescriber base now exceeds over 30,000 healthcare practitioners. And the one thing that I didn't mention that's not on the slide is we recently introduced our direct-to-consumer advertising on connected TV on September 22 and further enhanced that on October 10 by being on channels such as Disney+, Hulu, et cetera. Next slide. So we've really been strengthening our patient reach and market access, as I mentioned. We're driving awareness through innovative digital campaigns and broadening reimbursement coverage. As I mentioned, our award-winning Lipid Lurkers, we've started our connected TV campaign. And I can tell you, we thought that we would have -- well, our target is 18 million impressions. We already have shown greater than 6 million impressions in the beginning or since October. So what that means is that these are the number of people are actually watching this commercial. It's a non-skippable commercial, it's 60 seconds. So we're really creating a lot of consumer awareness and consumer activation through this commercial. From an access perspective, we have achieved 87% Medicare and 86% commercial approval rates. And this has moved significantly higher, especially since we've introduced field reimbursement managers. The co-pays on average are $29 and $36, respectively, for a 30-day supply. And this really reflects the growing payer confidence and improved access for patients. As a matter of fact, I think the easiest way to think about this from a commercial perspective, 9 out of 10 patients can get our drug. And from a Medicare perspective, 8 out of 10 can get our drug. It really reinforces the fact that getting NEXLETOL and NEXLIZET has never been easier. So we've created a lot of momentum as we get to the end of the year. We've continued our investment in our -- both our digital marketing to expand our reach and drive sustained growth. I can tell you we're already off to a fantastic start in the fourth quarter. And a lot of that was due to investments that we made in the third quarter. We're confident that these programs will continue to really fuel our performance. And again, we're really excited about the future as it relates to Esperion moving forward and excited about this that we're doing today. And with that said, I'll turn it over to LeAnne. LeAnne?

Thank you, Sheldon. And thank you all for attending today, and a special thank you to Drs. Patel and Rodriguez for taking time out of their busy schedule, especially on the heels of the American Heart Association meeting. So really, I want to spend some time today just providing some background to serve kind of as a framework for us to have a really robust discussion with both physicians. So next slide. So let's start with the definition of statin intolerance. So the National Lipid Association defines statin intolerance as one or more side effects associated with statin therapy, which either goes away or improves when the dose of the statin is reduced or discontinued. And NLA indicates that up to 30% of U.S. adults experience some degree of statin intolerance. So if you look here at the bottom, it's really a spectrum. From the left side, we have patients who have complete tolerance. So they have the ability to tolerate the statin at the therapeutic dose needed. Oftentimes, we think of these patients as moderate or high-intensity statin. Partial intolerance is the inability to tolerate a therapeutically required statin dose. So these patients may be on a low-dose statin, maybe some alternative dosing, every other day dosing. And then complete intolerance is the inability to tolerate a statin at any dose. Next slide. So we know now really well the risk factors for statin intolerance. And I want to highlight just a few here on the left side. Females are at increased risk for statin intolerance as well as older individuals. And these are really two groups of patients that really need LDL-lowering therapy who -- if you have high LDL-C. We know that females are underdiagnosed and not treated aggressively as males. And we know that as individuals get older, it becomes a challenge to treat individuals because of just complications you have as you get older in life. So for someone experiencing statin intolerance with these patient characteristics, it becomes even more of a challenge. Statin intolerance can affect quality of life. The most common symptoms that are reported are statin-associated muscle symptoms, although there are other symptoms and signs that the patients report that have statin intolerance. Next slide. The most concerning thing, of course, is that patients with statin intolerance remain at high cardiovascular risk. So statin intolerance contributes to non-adherence. About 29% of patients discontinue their statin within the first year of having -- based on statin intolerance. We know that patients with statin intolerance compared to those with high adherence to statin have an increased risk of about 50% of having coronary heart disease or a recurrent myocardial infarction. So the National Lipid Association has really recognized this risk in cardiovascular disease in this subset of patients. And so their recommendation is as the physician is trying to identify a tolerable statin dose, they should consider starting non-statin therapy. Next slide. So I want to talk about another issue that's related but is distinct, and that is statin refusal. And this is really becoming a growing challenge. What I mean by that is when a patient rejects a physician's statin recommendation, it's often due to fear of side effects like muscle pain or concerns about long-term safety or the disbelief in the proven benefits of statins. If you look here to the left, this is data from a recent large study in the United States, where it was in 24,000 statin-naive patients. In that group, 20% or 1 in 5 people at high CV risk did not accept their initial healthcare providers' recommendation for statin therapy. Now what that means is it's going to take longer time to get to goal. And so these patients remain also at high CV risk. If you look on the right here, you can see from the same study in the patients who accepted their healthcare providers' recommended statin, they were able to get to an LDL less than 100 in about 1.5 years as opposed to almost being 4.5 years in patients who did not accept their physicians' recommended statin. Next slide. So turning now to bempedoic acid. This is really a therapy we developed here to address statin intolerance. What do I mean by that? Well, bempedoic acid is a prodrug. And in order to get activated, it requires the enzyme ACSVL1. That enzyme is not present in skeletal muscle. So therefore, bempedoic acid is not active in skeletal muscle, and we've proven this in studies we've done. So bempedoic acid targets the liver or the hepatocyte. There, the enzyme ACSVL1 is present. It activates bempedoic acid in which -- at which point bempedoic acid inhibits ATP citrate lyase, which is in the cholesterol synthesis pathway. It prevents the substrate citrate going to acetyl-CoA. So you are disrupting that cholesterol synthesis pathway. It's above where statins act. So just like statins, bempedoic acid then indirectly increases the LDL receptors to grab more cholesterol from the blood, thereby reducing cholesterol levels. Next slide. So the bempedoic acid clinical development program was really unique. And I say that because we evaluated the drug across the full spectrum of statin use. So this table here represents the Phase III studies we did with bempedoic acid. So the first two in blue are CLEAR Harmony and CLEAR Wisdom. In those two studies, 90% of patients were on a moderate or high-intensity statin. The next two CLEAR Serenity and CLEAR Tranquility were performed in patients with statin intolerance, where 18% were partial intolerant and 82% were complete. The 053 trial was the bempedoic acid plus ezetimibe registration trial to support NEXLIZET. That trial actually had about 2/3 patients on moderate or high intensity, 1/3 with complete statin intolerance and a small portion also of partial intolerant patients. And then finally CLEAR Outcomes, of course, is the only study even out there, outcome study in patients with statin intolerance. In our study, we had 78% with complete statin intolerance. So of course, in all of these studies, bempedoic acid significantly reduced LDL cholesterol. And then also significantly reduced hsCRP. And I wanted to highlight that there is a recent scientific statement put out by the American College of Cardiology around inflammation and cardiovascular disease, which really highlights the importance of measuring hsCRP in both primary and secondary prevention patients because it is an independent risk factor. And even irrespective of LDL-C, if persistent elevated hsCRP above 3 persists, this really puts patients at increased risk of cardiovascular disease. Within this statement, bempedoic acid is mentioned, and it's commented that it lowers hsCRP between 20% and 30%, which is really a similar magnitude as LDL-C lowering. Next slide. So I just wanted to mention the CLEAR Outcomes used a real-world statin intolerance definition. So in this study, patients could have failed two or more statins at any dose or one statin at any dose and unwilling to attempt a second statin or they were advised by their physician not to do so. And as a reminder, we did allow partial statin intolerance, which was defined as having an average daily dose below the lowest dose you see here for each statin, which is generally the starting approved dose. Next slide. So just quickly, I wanted to remind everybody of the data from CLEAR Outcomes, which, again, the only outcomes trial in patients with statin intolerance. We had close to 14,000 patients, 30% were primary prevention, 70% were secondary prevention patients. Bempedoic acid significantly reduced the primary endpoint, which was a MACE composite 4 of CV death, nonfatal MI, nonfatal stroke or coronary revasc by 13% compared to placebo. You can see that on the left with the number needed to treat 63. You can start to see the Kaplan-Meier curve start to separate at about 6 months. And then on the right, you can see, and this is based on our statistical hierarchy, MACE-3 was reduced by -- significantly by 15%, nonfatal MI 27% and coronary revasc by 19%. Next slide. And as a reminder, in the 30% of our patients who were primary prevention patients, we saw a greater reduction in the primary endpoint and all of the secondary endpoints as well. So MACE-4 was reduced by 32% compared to placebo. Again, you start to see those curves separate beginning at 6 months. On the right here is the statistical hierarchy in order. So we see MACE-3 is reduced by 39%, nonfatal MI is reduced by 37%. And even when you get to cardiovascular death, you see a hazard ratio of 0.57. Now the study was not powered to detect all of these events in primary prevention patients. So this data is not type 1 controlled. Next slide. And this is to point out that the safety has been well demonstrated with bempedoic acid. We had almost 10,000 patients receive bempedoic acid across our Phase III trials, which demonstrated very well tolerable and safe product compared to placebo. And I'll also mention that starting in the U.S. in 2020, our products have been available. They're now approved in 41 countries. So we continue to get robust safety data from a post-marketing perspective, really supporting the benefit risk of bempedoic acid. Next slide. Okay. As Sheldon mentioned, we were really excited to see the ESC/EAS guideline update in August of this year, which really highlights the importance of non-statin therapies and specifically bempedoic acid. And so non-statin therapies with proven cardiovascular benefit, including bempedoic acid, received a Class 1 Level A, the highest recommendation that was alone or in combination for patients unable to take statin therapy. And bempedoic acid specifically received a Class I level B in statin-intolerant patients. What I think is really nice that was included in the guidelines is this figure to the left, which really shows the efficacy you can get with bempedoic acid in combination with all the available therapies alone or in combination with ezetimibe, statins and even PCSK9. So the clinician has a lot of flexibility in getting that patient to goal. Next slide. And this is my last slide. So this last slide is really to let you know that Esperion is very dedicated to the educational component around the risks of statin intolerance and that there are alternatives. So we have developed material, as you've heard Sheldon say for physicians, for physicians to use with patients and direct-to-consumer, so direct-to-patient advertising. So we're really committed and proud of our educational components. And I think next slide. Yes. Okay. Great. So that is my last slide. So what I want to do now is open it up to discussion with Drs. Patel and Rodriguez. And what I would like to do is have you both start out. If you could just provide a brief background, including your clinical practice, that would be great. So Dr. Patel?

Good afternoon. I'm Dharmesh Patel. I'm a cardiologist, I think, represents many cardiologists in the country. I'm on the trenches seeing patients every day. I'm in private practice with an academic affiliation. I'm seeing patients from Memphis, Tennessee, Mississippi and all around the Southeast of America, the heart belt, unfortunately, of the United States. And I serve one of the sickest states in the country. So heart disease is important and really excited to be on this call. So thank you.

Thank you so much for the invitation. I am Fatima Rodriguez, and I'm a preventive cardiologist at Stanford University. So I lead our Lipid Clinics. I see a lot of patients with statin intolerance, and I have an academic practice. So again, a lot of -- many of the patients that I see are referred especially because of inherited lipid disorders or because of prior intolerance to statins.

Thank you both. So I think what would be really helpful is just to kind of start off by getting your perspective on the scope of the problem, statin intolerance, statin refusal. If you could speak from your experience and also what you know even as a researcher, but also your clinical practice. And if there are certain patient characteristics that you've seen, it'd be great to hear your experience. Dr. Rodriguez, do you want to start?

Sure. I'm -- again, I'll have to just admit that I have a very niche practice because I lead preventive cardiology. So by the time patients come to me, many of them have tried statins before and are unable or unwilling to take statins. I'll say that I've been in practice as an attending for about 10 years, and I used to spend a lot of my time trying to try different statins, different combinations, different even days, every other day dosing. And now that we have so many drugs available to lower LDL, I don't do that anymore, and I really focus on that figure that you showed from the ESC guidelines, which is what agent can we use that makes sense for this patient to lower their risk and that risk is really proportional to a degree of LDL lowering.

Yes, I'll piggyback, Fatima, I don't know how you feel about it, but our patients appear to have a stronger perception when they walk into the doctor's room now about what they will and what they won't take. I'm not sure if it's social media or what have you, but a lot of my patients who were taking statins don't want to take statins now. I think it's really important, as Fatima said, we now have so many therapies for LDL lowering. I was really excited about bempedoic acid. That was the first oral LDL-lowering therapy since ezetimibe in 2002. So it was very welcomed. And the fact that it was -- had indications or data in primary and secondary prevention, I really thought that was great.

Great. Thank you both. So just kind of continuing around the patients you see, what are the common reasons you hear why patients maybe won't -- if they won't start a statin or if they're ready to stop? What do you hear?

Yes. And I really love the way that CLEAR Outcomes trial was designed because it was -- they're either unable or unwilling. And again, we know that's very, very common in clinical practice. I think many patients are -- even if they don't have actual side effects, even perceived side effects are really important. And for a drug that's a daily drug that's meant to take lifelong, adherence is a huge issue. And for whatever reason, again, it could be side effects. And I say, I think in my practice, probably 10% of patients have true statin intolerance as defined by the definitions that you discussed. But a much larger portion have I think some sensitivity, some intolerance or some unwillingness to take the statin. And those are the patients that I worry about most because we know that not being adherent to an LDL lowering agent, whichever it is, is associated with adverse outcomes. Women absolutely are much more likely to have statin intolerance and that's something I see in my practice as well as patients who take -- many other conditions have other medications, which is very common in the secondary prevention and also in the primary prevention groups.

Yes. I think what I love about the CLEAR Outcomes trial is it really represents the patients I see. As you said, Fatima, 46% female, 40-odd percent diabetics, some patients on a low dose of statins, 1 in 5. I just love the fact that it was one of the first trials that highlighted females, first and foremost. And on top of that, I just think it truly highlights what we see in primary care and in secondary care. As a cardiologist, I'm seeing primary care, too. The worried well or the patients who don't have access to the primary care doctor, so I feel that the trial represents best the patients that I see on a day-to-day basis.

Okay. So then maybe we talk a little bit about the management of these patients, right? So you've got them there. What do you do? Kind of what's your algorithm to train these patients? And does it differ for primary versus secondary prevention patients?

Absolutely, because I think the data is very compelling across all the studies that have been done across therapies. The real enemy here is LDL cholesterol and we're trying to lower it. And the lower is better. Of course, the degree of lowering is proportional to your degree of baseline risk. So the strategies are more intensive for those that have a higher LDL. I see a lot of patients with heterozygous FH, patients who've had a clinical ASCVD events. We learned over the weekend at the American Heart Association that even patients that just have coronary artery calcium to atherosclerosis are a very high risk of events, but they're targeting the LDL. It's all about bringing that LDL down. And we fortunately have many tools to do that, and NEXLIZET is one of those tools.

Yes. I think we're pushing to get numbers back on track and get some national qualities about numbers. I think LDL levels are very important. And I think what we are learning is the early you start therapy and the longer you start therapy, the better you do overall. So I think the census I felt from the AHA was let's start earlier, let's start more aggressively and that will downstream, reduce further cardiovascular events, even in "the people that have not had prior cardiac events."

Yes, absolutely. Okay. Great. So for NEXLETOL and NEXLIZET, are there particular -- I guess what do you -- where do you see our products most valuable? And how do you use the products? And if you could also comment on your experience from an effectiveness and safety perspective, that would be great.

Well, I think it's clear that this drug was designed for statin-intolerant patients. And again, I tend to -- with unable or unwilling to take statins, which is a large portion of patients. Even though some patients are able to take a small amount of statin, and again, that's helpful as an add-on therapy. In my practice, I almost always use it in combination with ezetimibe, so NEXLIZET, and we saw that's pretty impressive LDL lowering of 38% on average, some patients more, some patients a little bit less. It's a great oral alternative to statin, and it's really the only oral alternative that is available, especially for our primary prevention population. Very well tolerated. Again, access issues have definitely improved over time, and we've seen that in our practice where really the patients who need them are able to get it without many issues from the insurance companies.

Yes. And Fatima, I don't know how you feel about this, but I love the fact that it's diabetic neutral, maybe even favorable, we can't say that, but it's at least diabetic neutral. And then, of course, the fact that well, it's very well tolerated. And I tell my patients, this is a therapy that basically is not broken down by the skeletal muscle. So you should not be getting some of those anticipated side effects that we have been seeing with statins. And the other fact I was trying to get back to was the hsCRP as a clinician, inflammation drives atherosclerosis. And I think when I speak to my colleagues, everybody agrees the fact that hsCRP certainly is a predictor, at least enhancing risk factor from the ACC guidelines for atherosclerosis. We all believe that. And the fact that bempedoic acid does reduce hsCRP by about 23-odd percent, I think, is very well received by me and my colleagues, Fatima, how do you feel about that?

Yes, I agree. And I'm not so sure outside of the preventive cardiology world, how many people know this. So I do think it's important that we raise education around the CRP. But certainly, in our community in preventive cardiology, Dharmesh and I are part of the American Society of Preventive Cardiology, where all of us think about this. But certainly, inflammation is something that is one of the core causal processes that cause advanced atherosclerosis. So anything that we can do to help lower CRP is important. And I have many patients who -- again, that is a true side effective status, and I tell my patients that it can -- especially in people who have a tendency towards diabetes, prediabetes can raise your hemoglobin A1c, especially at the higher doses. So for many of those patients who are otherwise doing everything they can and they're having that bump in their glycemic index, this is a really great alternative.

Go ahead.

We expect that prediabetic, that patient is not "diabetic" yet. There's a lot of those patients in primary prevention that really weighed towards -- against a diabetic pro therapy rather than something that will at least keep the A1c neutral, if not even lower slightly.

Okay. Good. So I'm hearing it sounds like that in terms of differentiating aspects, mechanism is one that's important. HsCRP reductions is another one and neutral on diabetes. Is that safe to say because...

That's very safe to say. I think as Fatima mentioned, in clinical practice, I know half the time we may use NEXLETOL. But in clinical practice, we're using NEXLIZET predominantly with a 38% reduction in LDL, which is quite substantial. And certainly, as has been said, we may use it as monotherapy, we may use it as a backup on the statin therapy, which is a reduced dose. But the combination works very well. We know from the like the GOULD data, 36% of females and 48% of males who are high risk are stuck on monotherapy. And so this is where I really welcomed bempedoic acid because it was another adjunct of therapy, which could further reduce LDL further. And I think it'd be fool to think that statins are the end all be all of everything. We know this. I mean 84% of patients who have had an event will not get to goal with just simply statin therapy.

Yes. And I think we certainly moved that direction with blood pressure management, [indiscernible] therapy, focusing on the tailoring really the level of LDL lowering with the intensity of therapy. And especially as we get -- we really have these lower LDL targets, even in a patient that can tolerate statins, it's maybe not enough for many patients, especially depending on the baseline LDL level, you need adjuvant therapy. So the combination and even combination therapy off the bat is something that we're moving to in our practice, certainly endorsed by the European guidelines to really not -- you don't have to wait to get somebody see how they do because we know that clinical inertia, the waiting for LDL to come down, sometimes we never have the opportunity to intensify therapy.

This is no different to hypertension or diabetes. It probably will take combination therapy attempts to get to goal, just like in hypertensive, 67% of patients use combination therapy. I think it would be fair to say that most of our patients will need some combination of therapies.

Okay. And do you -- you mentioned -- like you said, the ESC guidelines were really supporting combination therapy. Do you think the U.S. guidelines will follow suit with combination therapy?

I think the U.S. guidelines will endorse lower LDL targets and again, focusing on LDL as the quality metric. And now that we have so many different therapies, especially therapies like this that have outcomes that have proven cardiovascular benefits, then the guidelines will just by definition, require the use of non-statin therapy, sometimes upfront in order to be able to get to LDL levels under 55, which I think will be the goal for many of our patients in either a very high-risk primary prevention or secondary prevention. But the European guidelines do what I do in my practice, which is they go even lower and LDLs under 40 for very high-risk patients, which is what we do in our practice, but I would say is off-label with the U.S. guidelines.

Okay. Let me ask you this, like in the -- with current approved therapies, how much is having an oral option, trying an oral option important to your patients? And does that differ in primary prevention patients versus secondary?

Absolutely. And I think it's positive that there are many options in preventive cardiology for us to lower LDL. But many patients are fairly close and they -- and just starting an injection is just not something they're interested in every 2 weeks, self-administered or even the inclisiran is obviously another option, but that doesn't have outcomes data, like coming to the healthcare facility. So you're just like you just need a little something, you need another pill, I mean another pill is obviously much easier. And it's -- almost all of my patients, I'm sure Dharmesh feels the same way, take pills. So that is not disrupting the routine in any way. It's just adding one more pill. And again, for me, I tend to use NEXLIZET. So that is actually a combination pill to really bring that LDL down.

Yes. I mean I think -- I would not be honest if I didn't say that GLP-1 agonist did change the perception of injections. So they have certainly changed it a bit. But again, most patients do not want to take an injection once every 2 weeks or what have you. I think they prefer taking oral therapy.

And I think the difference with GLP-1s, I completely agree with Dharmesh, most of my patients don't want to take statins, all my patients want to take GLP-1s. So I think there's just something that they feel it, they see it. You don't feel cholesterol until you have an event. You don't -- again, you're not getting repeat lipids if you're not big -- you need that feedback. So it's a very different patient experience. We've made cholesterol very confusing to our patients in terms of the ratio, so like I have a good -- I just saw somebody and they're like the lab value said my LDL was okay. But we know that's actually the normal for -- which is actually probably even too high of LDL under 130 for a high-risk patient is obviously not acceptable. So we've made it very confusing, and I really appreciate all the work you're doing to try to educate our patients around the importance of lowering LDL to improve cardiovascular outcomes.

I think another message is a lot of my patients will say, well, I'll just diet and exercise in primary prevention. But we know that only 25% of your cholesterol synthesis is from what you eat. 75% of your cholesterol synthesis is from what your liver makes. So having those messages and those meaningful discussions with your patients also changes their perception of cholesterol, is not necessarily a lifestyle issue. It's sometimes more genetic and what your genetics are.

And I just had -- and that's an important message for patients, and we've seen this with the lipoprotein A that they're like, that's not my fault. It's just my body makes so much lipoprotein A. So I just had a patient and I saw in clinic last week who's lost quite a bit of weight on tirzepatide, no change in LDL. LDL is 120, now it's 119. So that was a real eye-opener for this patient that they're like, it's really not lifestyle. It could not be doing better. They've lost weight, they're exercising, so their liver is synthesizing too much cholesterol. And I think that was actually a very motivating factor for our patients to start LDL lowering therapy.

If my memory does serve me right, Fatima, I think those GLP-1 tests, the LDL reduction was like 3% or something if my...

Very minimal even with weight loss. But I think we see this, right, that hypertension tends to respond really well, diabetes, for sure, with weight loss. LDL cholesterol, in particular, not so much. I mean -- and again, it's triglycerides definitely, but I see this a lot in my practice that -- but there's always, always that human, let's give it a try. I really want to try diet and exercise, but I don't want to fail and have to take a medication. So hopefully, just raising awareness on the fact that your body is making too much cholesterol. And even normal amounts of cholesterol, it may be too high for you, and this is a completely modifiable risk factor that we can control with safe and tolerated medications.

You're right. To your point, the NLA guidelines just said recently that a level of -- LDL level of 10 to 40 is okay.

Yes. How low can you go? I think that's another one that there's no danger to having very low cholesterol. I always tell my patients that the main side effect is that you live longer.

That's right.

That's good. So sticking to kind of the path around education. And I know you all don't have much time at all. But if you have a patient who you're struggling with the statin challenges of following what you've recommended or they have statin intolerance and can't take it -- what are some -- what do you tell that patient to try to get them to now do what you want them to do and understand their risk?

Yes. And I'm sure Dharmesh agrees with this. I think one of the most powerful tools that I use in my clinic now is imaging. So things like a coronary artery calcium scan. Because I think when you plug in numbers in risky equations, particularly for women, and particularly for younger adults, those numbers are not very impressive. They're hard to interpret. People like to think about proximate risk as opposed to 10-year risk and 30-year risk. So I often use imaging tools and usually imaging that they've already had in our health care systems to show them the process of atherosclerosis. This is your heart. You just had a CT scan done for another reason. You have plaque in your arteries. And that just, well, what is plaque. That is what causes the buildup of a plaque in your arteries causes a heart attack, but we can help fix this. We can make -- stabilize this plaque, prevent heart attacks. So to me, that's been a really powerful tool. And again, like I mentioned earlier, I've changed my practice over the past couple of years where I don't -- it's great to have some statin at the highest dose possibly tolerated. We know these drugs are safe. They've been around forever, great data. But whatever that is, even if it's 2.5 of rosuvastatin is better than nothing, but I quickly pivot and say, if that's not an option, let's not wait until I see you in 6 months, let's go ahead and get the ball rolling and start another therapy.

Yes. And I tell my patients, these therapies are your chemotherapy for your heart. I mean if you had a cancer, you take anything that would "solve it." But we seem to think that cancer kills more people than cardiovascular, absolutely not. The complete opposite. Cardiovascular is the #1 killer in the United States. And as Fatima eloquently said, right now in cardiology, things are changing really, really quickly. We are now having technologies that can tell us how patients are truly doing within the vascular beds. So it's changed because we know the data up to 50% of patients have no symptoms before their first heart attack. 63% of those patients are not even taking any lipid-lowering therapies before they quote, "first heart attack." So there is so many patients out there who we can risk stratify with these different technologies now. Talk about the amount of narrowing, the characterization of the plaque, is it soft? Is it hard? And hopefully, all these pieces of information will be able to fast individualize therapy to the individual patient, more like a personalized therapy approach. And so all these therapies that are out there will have a role and a place in our patients for sure. The number of lives that will be affected are so huge. We're not doing a good job just doing primary prevention. We're doing an awful job in secondary prevention. The amount of potential here and opportunity is unsurmount.

Well, this has been fabulous and your passion, your expertise, your knowledge just comes through so great. So I've loved the discussion. I think I'm sure there's lots of questions from our audience. So I think what we'll do now, operator, is turn it over to you to kind of facilitate the questions.

[Operator Instructions] Our first question will come from Paul Choi with Goldman Sachs.

Just for both Dr. Patel and Dr. Rodriguez, can you maybe provide some background information for us on how many -- what percentage of patients at your respective institutions are currently on NEXLETOL or NEXLIZET in terms of the eligible population or percentage of total patients that go through your institutions? And my second question is, as you think about the use of NEXLETOL and NEXLIZET in the statin-intolerant population, the drug and other modalities have been around for a few years. Can you maybe comment on what you think is the biggest barrier to adoption? Is it price? Is it insurance? Is it awareness? Any color from your perspective and your experience would be helpful.

Great. I was going to see if I could look it up with like a search tool. I would say that I have a -- my practice is probably not representative of the U.S. eligible practice because I have a lipid clinic and people that can't tolerate statins tend to preferentially come to my clinic. I would guess that probably the use of my patients is around 20% of my patients are some sort of bempedoic acid product, it probably -- it's certainly much, much lower across my institution. And that's a little bit because of awareness, and this is really across all non-statin therapies, even ezetimibe, right, that's been around for a while and it's generic because of a lack of awareness of the -- it takes it -- I just read somewhere that it's like it takes 10 years from a guideline to be released for full implementation. So -- and again, we're cardiologists, we're a preventive cardiologist, so we're a little bit more niche. Even within our cardiology community, I get a lot of referrals from general cardiologists to say, "Hey, my patient can't tolerate a statin." Can you just -- can you help? But because we have really good data on primary prevention, this is exactly the medication, and it's an oral medication, it's an easy medication to take that I think we really need primary care doctors to be familiar with, to be comfortable with. We -- I'll tell you that everything that we do for patients from the clinician side, it's really how easy it is to get and the buy-in from the patient. And a lot of us, I mean, unfortunately, I don't do the prior auths myself or the paperwork myself, but I often will say that it's the ease of getting the drug to the patient and explain to the patient that this non-statin option is available.

Yes. And if you just about population-based medicine, I mean, you've got 40 million to 50 million adult diabetics out there. And this really is -- Fatima and I represent the very top of the pyramid. I mean the amount of people that could and should be on this therapy is unbelievable. If you just simply put the diabetics, for example, 40 million to 50 million diabetics, LDL goal should be less than 70 if you have one risk factor. I can guarantee you that 50%, 60%, 70% of those patients may not be at goal. I'd say 50% aren't even on lipid-lowering therapy, just to give you some general population-based medicine. We can't even get not more than 20% of patients who've had a cardiac event to a goal of 55 just to give you some perception, a person that's had a heart attack, only one in five of them will get to the ECDP guideline threshold of 55. So when you talk about primary care, the problem is even bigger. And just being very honest, healthcare professionals are seeing lots of patients every single day. It's not just cholesterol that's on the problem list. There's about five to seven things going on, diabetic with arthritis with heart failure and sleep apnea. So as healthcare professionals, we sometimes lose that physician inertia being honest and a little bit of physician fatigue. But I think the message about we have therapy for primary prevention in those higher-risk subset populations, I think that message will go a long way.

Yes. Maybe I would just add. Dr. Patel and Dr. Rodriguez, it's not so much -- and Paul, not to redo your question, and thank you for your question. It's not so much how many patients are on the drug, but how many patients could be. And it speaks to -- and I think I've heard this at every seminar since I am on Zocor back in 2003, we collectively aren't doing a good enough job to educate patients, activate patients, et cetera, so that they know that they have this silent killer. They don't feel anything. They feel okay. But meanwhile, here they have a problem and that's why we went over some of the things that we're trying to do as well to activate consumers, educate them, et cetera, and create more of that awareness. So this is something I think that will continue for a very long time regardless of drug.

Yes. I couldn't agree more, Sheldon. And I think the important thing here, there's obviously a lot of different drugs either in development or already available. The enemy is LDL. And I think if every company raises awareness about LDL being a completely modifiable risk factor, a causal risk factor for heart attacks, stroke, PAD that's really the win. And I'll tell you that we're just not doing a good job at this. I do a lot of research on this in guideline gaps like why are we just not doing this. And I even do some -- that we look at medical records and we try to understand this rationale why are physicians -- there's is so -- lack of awareness of new LDL targets. Particularly in our stroke patients, people think that you need LDL cholesterol for the brain and all these myths, right, that have obviously been debunked. So even within our own physician community, there's a lot of lack of understanding, even cardiologists, my colleagues who do something else, electrophysiology, general cardiology. So I would say that Dharmesh and I are very passionate about lipids, and we're aware of all the therapies and all the different options, but that's just not the case. But I think bempedoic acid in particular, has a huge reach in the primary care population, potential that probably has not been realized because it's oral, it's easy. There's really nothing that you have to worry about. And again, it's the next obvious kind of add-on therapy for primary prevention when you're trying to get someone to go or in those patients who are unable or unwilling to take statins.

As soon as I say it's not a statin, patients' ears perk up for whatever reason that is, I'm just letting you know that's what happens.

It's the anti-statin campaign on TikTok.

Yes. No, it's pretty unbelievable.

Your next question will come from Joe Pantginis with H.C. Wainwright.

Can you hear me?

Yes.

Great. So look, as NEXLETOL and NEXLIZET building in visibility, especially after CLEAR Outcomes, I have a two-pronged question. So going back to the chart that LeAnne showed earlier with all the different combinations that you're looking at, number one, how many combinations can you really try with one patient, number one. And as you're looking at new potential assets coming through, I would love to get your thoughts on the recent -- from this weekend, very exciting data at Merck, Amgen and Ionis, for example, how do you think NEXLIZET and NEXLETOL might fit in with those assets and how BPA might be complementary, sorry, with many of the existing and future assets.

Well, I think, I'll just say for me that it's such an exciting time to be a preventive cardiologist because we do have so many tools in the toolbox, not just statins that are either existing or are in the pipeline. I think a lot of it is going to be personalized because there are so many patients with hyperlipidemia. There are so many patients at high risk of cardiovascular disease that I don't think one is going to just take over everything because it really has to be personalized hopefully in the background of statin therapy. We even heard this weekend at American Heart Association, the extreme option, which is one-and-done gene editing, right, for LDL. I'll tell you that the uptake of that will be quite low from the beginning, maybe for the highest risk populations and everything, always starts with the highest risk populations when you start developing a new compound and then eventually makes its way to other populations. But I don't think it's going to take away from bempedoic acid. I don't think it's going to make it obsolete anyway. I think it's just going to raise awareness about non-statin therapies that can improve outcomes if these compounds end up having positive outcomes. So I think it's additive, and I think it's great. And people are going to say, "Hey, is it an oral option? Is it an easy option?" So I think a lot of those factors are how is it administered? How does it interfere with people's lives? What degree of LDL lowering because there is a real difference between degree of LDL lowering for the therapies if someone is almost at goal. And do they just need a little bit more than maybe just bempedoic acid monotherapy versus adding the NEXLIZET.

Yes. I think the data that came out this weekend was exciting. As you said, Fatima, everyone is going to be a winner, I feel. And one thing -- great thing about bempedoic acid is it can be used with any, I believe, of the therapies that will describe this weekend. Even the Merck data with the oral PCSK9 was good. Remember, you have to be fasting 6 hours before and not drink or eat anything for 30 minutes after, fantastic. The [ facility's ] data was data with high-risk patients who had not had a prior cardiac event. [ Entry's ] inclusion data was slightly different. The CAC score was 100. I think from the CLEAR Outcomes it was 400, different subsets of patients. But the great thing I noticed or I took back from that is even if you look at the primary prevention subgroup in CLEAR Outcomes, the diabetics, which was about 30-odd percent, when you look at the risk reduction in 3-point MACE and 4-point MACE, the [ status ] is 29 and 26. CLEAR Outcomes is 36 and 30. Even if you look at the CCT data looking at how "your therapy compares to statins?." You can see that in the primary prevention graph, the hazard ratio of 0.55 for bempedoic acid in primary prevention. So the point I'm trying to make is bempedoic acid is not going anywhere. If anything, personally speaking, I think it will be embraced more and more by healthcare professionals moving forward. I think our biggest issue has been lack of knowledge by healthcare professionals that this therapy can be used if and when.

And LDL targets, right? I think there's is still lot of -- the 2013 cholesterol guidelines were just set it and forget it. And I think the data that has come out across all these therapies has just really proven the LDL hypothesis that lower is better, longer is better. And again, adherence is really important. So this is -- I tell my patients, LDL is the same thing. I think about smoking. It's pack years of LDL exposure. So you need a therapy that you can tolerate over time to have that lower LDL over time.

Let's not forget what LDL lowering with NEXLIZET, I mean which is bempedoic acid and ezetimibe that's about 38%. That's the same efficacy as a moderate to high dose intensity statin. So it's not like 38% is pretty, pretty impressive in combination.

Your next question will come from Jason Zemansky with Bank of America.

Maybe a follow-up as far as other targets in dyslipidemia. But you mentioned a lot of hsCRP. How important is Lp(a). And does the fact that bempedoic acid doesn't seem to have an effect on this is that an issue at all?

I think it's good that doesn't raise it, right? Lp(a) is an exciting -- and again, there's been a lot of awareness about lipoprotein A likely being a causal risk factor for cardiovascular disease. There are ongoing trials across different companies for agents that reduce lipoprotein A by 80% to 90%. And I think those are the drugs, the specific drugs. I think that degree of Lp(a) lowering will be required if we want to test the hypothesis that reducing Lp(a) independent of LDL improves outcomes. And we don't not have the answer to that yet, but that's something that I'm very excited in the future preventive cardiology because, again, that's a risk factor that's entirely genetic that can potentially be modified. I don't think, again, you may be referring to the fact that the PCSK9 inhibitors lower Lp(a) by 20% or so. That is not -- that would definitely be an off-label use of a PCSK9 inhibitor for that reason. And the data so far, at least like the secondary analysis does not suggest that, that's a sufficient level of Lp(a) lowering. What I'll say happens in clinical practice is that Lp(a) is a clear risk-enhancing factor to drive lower LDL value. So if somebody has a high lipoprotein A, I'm going to be much more intensive with their LDL lowering.

Yes. I'm just as excited as I am scared about when the Lp(a) data comes out. I was part of those trials. I just -- let's wait and see as Fatima says, it's causal risk factor. Backing off what Fatima did say, PCSK9s do not affect hsCRP. Yes, we do know that bempedoic does reduce hsCRP, so does statins for that reason. So I'm -- all about inflammation, unfortunately, or fortunately, and I feel that inflammation is, I think, the crux of atherosclerosis progression. So I'd be excited to see what Lp(a) does, but it's not a slam dunk right now, far from it.

Your next question will come from Rick Miller with Cantor Fitzgerald.

Rick on for Kristen. Can you hear me okay?

Yes.

Yes, you mentioned -- to the doctors, you mentioned that at least some of your patients are on low-dose statin and either NEXLETOL or NEXLIZET. So how important could it be to have a fixed-dose triple combination versus just managing sort of multiple medications separately? And I'm asking, of course, because this is something that's sort of been talked about by Esperion and their partner.

That's a great question. And I've been a big fan of polypills forever. They just presented at the American Heart Association, a polypill for heart failure, in particular, in low-income settings to make things easy. It's good and bad. I think that it would make -- once you know a person can tolerate a specific combination, changing it to one pill sounds like a no-brainer, especially if that's even a lower dose that's currently available because I think you just need a little bit of statin. I tell my patients a little bit of statin, probably you get the most benefit from even just 5 milligrams of rosuvastatin. Less incremental benefit and a lot more of the potential side effects when we go up to, for example, rosuvastatin 40. But the one downside to that is that it's important to isolate the effect of things. So you don't -- once you throw the statin in there and especially for a drug that's for statin-intolerant patients, there may be a little pushback from patients. So I think that, that in practice may have to be tested in a different population, not necessarily a statin intolerant population or even just do 1 milligram, but like such a low dose statin that -- we still have a benefit, but not that would potentially cause side effects.

Yes, I agree. As we all know, the lowest dose of statin gives you 75% of your LDL lowering. So as Dr. Rodriguez has said, even rosuva 5 or 10 brings something to the table and increasing the statin thereafter just reduces your LDL by 6% each time you double up. So I agree, I'm all about combination therapy, Fatima. I do see your point about the side effects in that, but we are doing such an awful job capturing LDL reduction and getting to goal that whatever it takes at this point. And I think as has been mentioned on this call, just like diabetes and hypertension, it's not going to be one therapy, maybe two or even three. So the great thing about bempedoic acid is its best friend is ezetimibe anyway. And then they can be best friends with statin. So it's going to be in the equation somewhere...

Yes, you're right, it's oral, but I'll say the other thing is that clinicians -- but I think this clinician inertia, like I read this [Technical Difficulty] my colleagues discuss -- some people even acknowledge LDL not a goal. Discuss the next visit. What's the discussion? It's going to not be a goal next visit too. Let's wait for another -- there's therapeutic inertia. So I think this off -- right at the beginning, your LDL is 150. The chance of getting it to where it needs to be to start with is very unlikely. Let's start the combination. And again, we can predict this. We know that we saw that beautiful figure from the ESC guidelines. We know what medication can help us get to that desired LDL lowering. But that's not what is done in clinical practice. I think in clinical practice, people are very -- start something, then titrate and all those elements of needing to titrate and follow up are where we're losing people. We're losing opportunities to really increase lipid-lowering therapy.

If I could add, Dr. Patel and Dr. Rodriguez, we are currently developing a triple combination, and we're looking at a triple combination with both atorvastatin and rosuvastatin. And to your point, a low dose of a statin. And we've done the modeling, looking at low-dose statin plus NEXLIZET, and we see what the LDL efficacy can be. It can be upwards to 70% reduction just with a low-dose statin. And to your point, it speaks also to having that flexibility of the suite of options where you have this triple combination, you can use NEXLETOL on its own, you can use NEXLIZET. But I think also just going back to some of the remarks that you made earlier, gone are the days, and this is how ESC started, you may recall, of just using one therapy, as you mentioned earlier, to get to goal, you really have to look at how diabetes, hypertension has been managed. This is where lipid lowering is going. And I would say that we kind of saw that future coming and said, okay, how can we develop this polypill strategy. So we're really excited about it as we continue that development.

That's exciting, and that will serve the mantra of LDL reduction even better than what we have done thus far.

And patients do -- even though it's not true, do see it like as a failure to get an add-on drug. So when you put it in one pill, there's just like a psychology to that, this happens with hypertensive -- I think a lot of us -- I'll say, for antihypertensives prefer doing either low or medium doses of multiple drugs to kind of mitigate side effects. Patients hate this. So like can you just double my existing drug because it's almost like a failure. But when you change it to a combination pill, number one, we know it increases adherence, but also it doesn't seem like an added burden to the patients where you do kind of pill counts [indiscernible] patients.

I'm always bartering with my patients where I said, listen, I'm going to give you bempedoic acid and in return, you're going to stop your ezetimibe, so I'm giving you NEXLIZET. So I'm changing one pill for another, and they love it. They truly do love it. I mean none of us on this call like to take pills if we don't have to, but the less number of pills are better. And if you would give me something one in three, I'm more likely to take it than three separate pills. It's just a fact. And I think there's a perception about injections, too. I mean I don't think everyone is like, okay, yes, let me give -- take an injection medicine for the rest of my life for getting my LDL lower. I think people -- perception will be to take an oral agent first. GLP-1s are different. GLP-1s, as you said, Fatima, they give so many other effects, visual, psychosocial, whichever you want to call it. But when you're talking about cholesterol therapy, I'm not so sure.

And I would say this like anti-injections, anti -- anything that kind of gets deep in the cell sentiment is greater now than it was maybe historically, even though there's obviously exciting science in developing some of these therapies that are not just for LDL, but also for triglycerides and other factors in the atherosclerotic cascade, including lipoprotein A.

Fatima, I kind of want to ask you this question. The perception by the healthcare professionals, these days, we should fix diabetes, we should fix obesity, cholesterol is maybe not so important. But I recently learned that actually cholesterol management is probably the most important of the three factors treating the patients that we see in clinic.

Yes, there's a lot of data from the inter-heart study in terms of like the percent attributable risk for most particular myocardial infarctions. And LDL is the #1 risk factor that is modifiable, that is highly, highly modifiable that can explain a lot of that excess risk across populations. And to me, I mean, again, maybe biased but I think that it's so much easier to treat LDL cholesterol and to treat high blood pressure because high blood pressure, again, that's when you need a lot more patient feedback, a lot more visits, a lot -- it's more complicated. I don't -- I think we had historically made cholesterol management very complicated, and we still have some residual pieces of that from the past with these LDL thresholds are too high with this perception that if your HDL is high, you're okay. And I see this in clinic all the time, somebody has been told your ratio is fine, don't worry about it. But now it's pretty simple. It's about -- all about LDL, the lower the better, the earlier the better and the longer the better.

Great. Okay. Well, that was our last question. So first of all, I just want to thank both Dr. Patel and Dr. Rodriguez. Thank you so much. We really appreciate your participation, the Q&A as well. LeAnne, thank you for your moderation and also being a very big contributor in setting up the symposium. I think we're going to continue to do a series of sessions like this as we go into the New Year of 2026, but thank you so much. Before we close the session, I do want to mention, first of all, for those of you who have worn the uniform are wearing the uniform, past and present, thank you so much for the service to this great country. So happy Veterans Day to all of you out there. And also, again, thank you for tuning in to our session on statin intolerance today. Again, more exciting things to come with Esperion, tune in next week, we'll be in London as we head to Jefferies, the Jefferies Conference, after that at the Piper Conference in New York City and look forward to continue to share more information about the organization and what we're doing. Thank you so much. Have a great afternoon and talk to everyone soon.