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

Good afternoon, and welcome to Esperion's Virtual KOL event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on Esperion's website following the conclusion of the event. And now I'd like to turn the call over to Sheldon Koenig, Chief Executive Officer of Esperion.

Thank you very much, and good morning, everyone. Welcome to Esperion's Key Opinion Leader Day today with both LeAnne Bloedon, our Head of Clinical Development; and also Dr. Patrick Moriarty. I'd have the first slide, please. And if there is no slide, which I do not see, I will go through them by memory. So first of all, I just want to remind everyone that there is a forward-looking statement. So anything said today falls under our normal forward-looking statement and disclosure agreement. You can find it on our website. Just for some background, Dr. Moriarty is a Professor of Medicine at the University of Kansas Medical Center in Kansas City, Kansas. Go, Chiefs. He is the Director of Clinical Pharmacology at the Atherosclerosis & Lipid-Apheresis Center. Dr. Moriarty is a fellow of the American College of Physicians, the American College of Cardiology, the European Society of Cardiology, National Lipid Association, and he was a 2014-'15 President of the International Society for Apheresis. Dr. Moriarty has published well over 100 peer-reviewed articles and chapters, ranging anywhere from atherosclerosis to lipoprotein apheresis and vascular inflammation. So at this point, I will turn the call over again to LeAnne Bloedon, our Head of Clinical Development here at Esperion. LeAnne?

Great. Thank you, Sheldon, and thank you all for attending today. And a special welcome and thank you to Dr. Patrick Moriarty, who is taking time out of his busy day to speak with us. So I'm going to spend about 10 to 15 minutes talking about some of the unique aspects of our clinical development program with bempedoic acid. And I think this will be really nice to serve as the framework when we then get to the open dialogue with Dr. Moriarty. We're going to hear about his clinical experience with bempedoic acid and how he views our products in regards to place in therapy, okay? So Tiffany, if we can go to the next slide. When we were developing the clinical development program about 10 years ago, we had some of the same issues and challenges with unmet need that we have today. Atherosclerotic cardiovascular disease remains the #1 cause of death in the United States and globally. And recent metrics show that 44% of U.S. adults have cardiovascular disease or they're at risk of having a first event. And what's disappointing is that over half of these patients are not at the recommended LDL-C goal, which, of course, is a main risk factor for cardiovascular disease. And then when you think about adults who need treatment, up to 30% may be unable or unwilling to take recommended statin therapy. Next slide. So when we develop the clinical development program for bempedoic acid, we wanted to not only conduct trials that were needed from a registration or regulatory purpose, but we also wanted to make sure that we were evaluating patients that -- with all unmet needs, and really looking at populations that would take our products when our products got to the market. So you can see here, not only did we evaluate statins at moderate or high intensity, which is required by the FDA and the EMA, but we also evaluated bempedoic acid in combination with low-dose statin therapy and doses below that, and even in patients where they're [indiscernible]-tolerated statin was no statin at all. We were also committed to developing a fixed combination product with ezetimibe so that we could approach both causes of high cholesterol that is from the diet as well as the liver. And then finally, in terms of populations with high unmet need, we were committed to not only studying those that were required by regulatory bodies, that is patients with cardiovascular disease and/or heterozygous FH, but also patients who were primary prevention patients, those that had not experienced a first event, as well as patients who have partial or complete statin intolerance. Next slide, please. So this slide shows you the Phase III placebo-controlled studies, there were 5 of them, that we conducted to support our primary hyperlipidemia patients. So if you look at the far left column in blue, these are the 2 registration trials. This is your typical studies that our predecessors as well as those in current development are performing, which is evaluating the product in patients with cardiovascular disease and/or heterozygous FH. We studied that on top of a maximally tolerated statin, where 90% of patients in these 2 trials were receiving a moderate or high-intensity statins on top of other stable lipid-lowering therapies. If you look in the middle column, these 2 trials are where we are unique. We wanted to have committed trials that were evaluating our products in patients with partial or complete statin intolerance. Now what's also unique is the population. So we studied patients with cardiovascular disease and/or heterozygous FH, but also primary prevention patients. And then finally, if you look at the far right column, you can see the trial that supported the approval of NEXLIZET, which is looking at the combination of bempedoic acid with ezetimibe. And in this trial, we also had patients with cardiovascular disease and/or heterozygous FH, but also high-risk primary prevention patients. These patients were also on maximally tolerated statin therapy on the background of other stable therapies as well. Now if you look at the bottom 2 rows, you can see that across all of these studies, we saw statistically and clinically significant reduction in LDL cholesterol as well as high-sensitivity C-reactive protein. Next slide. Okay. Now this slide gets to our cardiovascular outcomes trial, the CLEAR Outcomes study. This trial is unique in several ways. First of all, it is the trial that validated that reducing LDL-cholesterol with bempedoic acid through inhibiting ATP citrate lyase does impact lead to CV risk reduction. It's also unique because we included primary prevention patients and as well as secondary prevention patients. And then finally, it's unique because it is the only trial where there's outcomes data in patients with statin intolerance, both complete and partial, which is really a group of patients who have a high unmet need. Now the primary endpoint was a 4-component MACE, which consisted of cardiovascular death, nonfatal and mine, nonfatal stroke or coronary revas. So in this study, which consisted of nearly 14,000 patients which were followed for over 3.4 years, we see a statistically significant reduction with bempedoic acid compared to placebo in our primary endpoint, with a hazard ratio of 0.87, which is a relative risk reduction of 13%. And if you look at the figure, you can see that the Kaplan-Meier curves start to separate as early as 6 months, showing the benefit of bempedoic acid. If you look to the right, you can see our MACE-3, which was our key secondary endpoint, resulted in a hazard ratio of 0.85 or 15% relative risk reduction. Looking at nonfatal myocardial infarction, there was a 27% risk reduction, and coronary revas resulted in a 19% risk reduction. Next slide, please. Now as I mentioned before, CLEAR Outcomes is the only non-statin FDA-approved drug with data in patients with primary prevention. So this data shows here what we saw in that group of nearly 4,200 patients. So looking at the same MACE-4 endpoint, you can see with bempedoic acid, there was a 32% relative risk reduction in MACE-4. This had a number needed to treat of 43. When you look at the harder endpoint of MACE-3, you then see a 39% relative risk reduction. And impressively, looking at cardiovascular death as a component, we saw a hazard ratio of 0.57, which is equivalent to a 43% relative risk reduction. You can see here from the Kaplan-Meier curves, as we saw in the overall population, also in primary prevention patients, you start to see that visual separation of the Kaplan-Meier curves as early as 6 months, showing the early benefit of bempedoic acid. Next slide, please. Now this slide looks at the risk reduction of major vascular events based on the LDL lowering of different populations in CLEAR Outcomes. And this is based on using methodology from the cholesterol treatment trials collaboration group, which has looked at patients who received statins in nearly 30 trials in NEAR and over 175,000 patients who received statin therapy. That group has concluded that for every reduction in LDL cholesterol of 1 millimole per liter, you get the 22% major vascular event risk reduction. And that is what's shown here in the dotted line. So when we look at data from CLEAR outcomes, we wanted to look at 4 different populations and see how our data compared to the statin data. So the blue box represents the overall intent-to-treat group, which consist of patients that were randomized to drug, irrespective if they stayed on drug or not during the trial. The green box represents the on-treatment group, which are those patients that did stay on treatment for the duration we participated. And we have the secondary prevention patients represented as a purple box and then primary prevention patients represented as an orange box. You can see that in the intent to treat, the on-treatment as well as secondary prevention patients, the level of CV risk reduction with bempedoic acid is similar to that achieved with statins. It's pretty much on the line for these 3 groups. Now when you look at the primary prevention patients, it is well above the line, suggesting that you get a greater CV risk reduction based on the LDL-C lowering in this group. And this is actually not that surprising based on additional data from the CTT group with statins. So let's go to the next slide. Now this is also data from the same cholesterol trials treatment collaboration group, and this is a forest plot. And what they did is they again looked at all of their statin data. But this time, they looked at patients without vascular disease, which is at the top, and they also looked separately at patients with cardiovascular disease. And so I want you to look at the top portion, which is primary prevention patients. The 2 rows I have highlighted in pink are showing you that in patients that are at lower risk, even within the primary prevention group, you get a greater CV risk reduction per 1 ml millimole per liter. What this suggests is that you get a bigger bang for your buck, if you will, in terms of reducing LDL-C cholesterol. It shows the importance of treating as early as we can in the atherosclerotic process, and that will give us a larger CV risk reduction based on the LDL-C lowering. Again, this supports what we've seen in CLEAR outcomes in patients with primary prevention, where we saw that larger CV risk reduction based on the LDL-C lowering in that group. Okay. If we go to the next slide. In terms of safety, we now have safety demonstrated in almost 10,000 bempedoic acid-treated patients across the Phase III trials I just reviewed. The data here is from CLEAR outcome because it's our largest and longest trial. So with exposure up to 6 years, bempedoic acid was generally well tolerated with a similar safety profile to placebo. You can see the first 3 rows here, when we look at any adverse event, serious adverse events or adverse events leading to discontinuation, we see that is well balanced with placebo. You see myalgia here because this is a population of statin intolerance, and we looked at muscle side effects, and myalgia was the most common side effect reported in both treatment groups. However, when you look at bempedoic acid versus placebo, you can see about -- it's about a 1% less in bempedoic acid. So there's no increased risk. When you look at discontinuation due to myalgia, it's also balanced with placebo. Now bempedoic acid is associated with small increases in uric acid based on a known mechanism that occur early, they're stable over time, and it's reversible upon discontinuation. But because of that small increase, we look at risk of gout. Gout reported in CLEAR outcomes was reported low across both treatments. There was about a 1% higher incidence of gout in bempedoic acid compared to placebo. When you look at the discontinuation rates due to gout, it was very low in both treatment groups, 0.1% and balanced. And then finally, in CLEAR outcomes, we had about 42% of patients, who, at baseline, were -- had pre-diabetes. And so when you look at the risk of getting diabetes in the trial, there was no increased risk with bempedoic acid compared to placebo. Next slide. And this is my last slide. So now we have data from CLEAR outcomes that is in our label, which we achieved in 2024, and the label has been updated to expand the indication. So -- and this is in both of our products. So we see that NEXLETOL and NEXLIZET are the obvious next step when you think about reducing CV risk. So if you think about when I first started this presentation and I talked about the unmet need, we have this available non-statin therapy that can address that need. It's -- again, they're the only products that are indicated with CV risk reduction in primary prevention and secondary prevention. And we get significant LDL lowering using an oral agent that can be used with or without a statin. If we go to the next slide, basically, I now want to open up the call to speaking with Dr. Patrick Moriarty on his real-world experience with bempedoic acid. So again, thank you, Dr. Moriarty for joining us.

Hi, LeAnne. Thank you for inviting me.

Yes. Good. So why don't we start out maybe with you just giving a brief introduction of your background as well as where you practice clinically.

Well, Sheldon gave a little bit background of my work, but I'm, as he mentioned, the Director of Clinical Pharmacology, which this division here at KU, started the Lipid Clinic in 1960. So the Lipid Clinic here for 65 years now. And we are involved with clinical trials dealing with dyslipidemia and so forth. But when I became Director about 25 years ago, I initiated lipid-apheresis program too, which is our device kind of like dialysis that filters your blood and lowers your bad LDL and LPL cholesterol by 80% in 2 or 3 hours. And we are now the largest center in North America. We treat more patients with this device in University of Kansas than all of Boston, New York, Chicago, L.A. combined even. It's a crazy amazing therapy that works lowering LDL and inflammatory markets and so forth. And we did, like I mentioned, clinical trials with bempedoic acid and a lot of other lipid-lowering medications. And we're quite active in this activity. And I'm glad to see your drug has come out, particularly for primary prevention, which I think is not being addressed more aggressively for atherosclerosis, and it should be like hypertension is not waited till someone developed secondary events from hypertension. It's treated right away. And I think when we look at atherosclerosis and risk factors like LDL, another -- it would be lipoproteins. It should be addressed right away. The earlier, the better to prevent the disease from developing.

Okay. Great. Yes. So can you tell us a little bit about the types of patients that you see clinically. And are they often referred to you?

We have a diverse group of patients and classically, we see a lot of patients with familial hypercholestemia, FH, with a genetic predisposed patients with high PLA, which is now being tested quite extensively now. Also, we see diabetic patients with dyslipidemia, tritriclycerides, low HDL. So we see a [indiscernible] of all types of patients and our referral base is primary care, cardiologists, endocrinologists and so forth. So we get quite a diverse group of referrals in patients.

Okay. Good. So when you think about your primary prevention patients and your secondary prevention patients, are there certain factors that play -- that come into play when you think about how you want to manage these patients?

Well, when secondary prevention patients are presented, we are more aggressive, obviously, because they've already had the event that we're trying to prevent another event, so we're getting very aggressive with them after that. And in primary prevention, we usually go low and slow to develop, depending on their age and their so-called risk in their need of lowering their risk factors as best we can. We have dietitians that look at their diet. I recommend exercise as a part of my regimen. I like to recommend a device called a water roller, which is device that uses 85% of your muscle groups that helps burn up 1,000 calories in 1 hour, so it's a good device. So it's a combination of pharmacotherapy and lifestyle that we aggressively add to our regimen of treatment for these patients.

Okay. Okay. Great to know. So maybe before we start talking about bempedoic acid, your experience there, let's talk a little bit about statin intolerance. So in 2022, the National Lipid Association released a position paper, as you know, that define partial and complete intolerance, with an incidence rate perhaps up to 30%. So just curious, how often you come into contact with these patients? And then also how that impacts how you manage them?

Well, we see quite a few statin-intolerant patients that referred to this, close to 50% actually. And I coin these patients in my clinic, delicate flowers. Because like delicate flowers, they need to be nurtured and delicately treated in order to grow. And there is a genetic predisposition to having statin intolerance, but that's a minority compared to patients who really see. I think most of it is somewhat super tentorial where they heard someone had a problem with the statin or their relative did or they have a high anxiety and aches and pains they are soon to be related to a statin. So we go very slow with these patients in sense of therapy. We'll put them on once a week statin to start of some of them, particularly with rosuva statin. It has a very long halfline, with very good success, and we published that 10, 15 years ago. But the consistency of statin intolerance related to that, as you showed in your trials, the placebo had a higher risk of myalgias than your product did. And I was the first doctor at the [IMC] alternative trial using a PCSK inhibitor. And we showed in that study with -- compared to placebo, that placebo was causing more adverse events than the drug itself. So statin tolerance is a very complex situation for patient population, and your product has been shown to be quite effective in our patients who have this history, and we tell them the mechanism of action being -- it's isolated delivered and it's a prodrug until it gets in the liver to be activated by the enzyme. Explain the pathophysiology and the pharmacokinetics of a drug really helps the patient compliance in certain ways.

Okay. Good. Good. So yes, so now maybe we kind of switch gears a little bit to talking more about your experience with bempedoic acid, either as NEXLETOL or NEXLIZET. So tell us a little bit how you utilize the products. And does it differ in different -- the populations that you treat, meaning primary prevention, secondary prevention or those with statin intolerance?

Well, we still follow the standard pathway of a statin first in patients, if they haven't been on the statin. And then we try to try -- if they've been on a statin with tolerance, then we'll do the topic dosing of maybe once a week or something of that nature. And if they have this intolerance that after 1 day of dosing of a statin, they have problems, we then move on to other classes like ezetimibe and then bempedoic acid. And then finally, we might -- if LDL is what we're needing to lower, we might add on a PCSK9 inhibitor as our fourth regime. So we stick kond of standard protocol with oral medications, with diet and exercise. And then eventually, if the oral medications don't work, move on to a higher, more potent and sense more invasive therapy with the PCSK9 inhibitors.

Okay. Okay. Good. So tell us, are there any differentiating factors with bempedoic acid that helps you decide in what populations or how to use the product when you're thinking about what [ nonstatin ] therapies you want to utilize?

Well, safety, as you brought up in your trial is one, effectiveness in a sense of what it does in the sense of lowering LDL, and third, it's a mechanism of action, not only lowering LDL, but you showed the lowering of CRP, which was quite dramatic. The CRP is a measuring of vascular inflammation. And when you look at vascular inflammation, to atherosclerosis, it's like looking at a fire and atherosclerosis inflammation is kerosene to that fire. So if you have inflammation in your vascular system with a atherosclerotic plaque, that further destabilized the plaque at the susceptibility to rupture by the inflammatory products that are in the vascular system. And your drug, as you showed, lowered the CRP quite dramatically, almost equal when it was in combination with ezetimibe. It was almost 1:1 LVL in the CRP reduction. And statins can lower CRP. Unfortunately, PCSK9 inhibitors don't. And additionally, as you know, we -- I suggested on the -- on the CLEAR trial -- the CLEAR outcomes trial, to look at other markers, particularly something called RDW, red blood cell distribution with, which is part of the indices and the CBC, it's a complete blood count, is also a marker of inflammation, but chronic inflammation. And additionally, it's a marker of increased blood viscosity, meaning your blood becomes more viscous when you have this high RDW in your system, which could be detrimental microvascular diseases. And RDW has been shown to be an independent risk factor for cardiovascular disease. In fact, in the ODYSSEY outcome trial using PRALUENT or alirocumab, I was the first author of a paper looking at RDW and the ODYSSEY outcome trial. And we found that the RDW level predicted cardiovascular mortality, irrespective of age, gender, LDL or hsCRP. Unfortunately, like CRP, PCSK9 inhibitors do not have an effect on RDW levels. And we found in CLEAR outcome trial that your product actually lowers RDW, and the lowering the RDW showed a significant correlation to the event reduction. We haven't published the papers. It was presented at the ESC in London this past September, but the publication is under -- we're working on now to get it out in the near future.

Okay. Great. Yes. Well, thank you for going through those -- some of those differentiating factors that kind of play a role into what products you choose to manage your patients. So can you talk a little bit about how well your patients on bempedoic acid have done, from an LDL-C lowering perspective as well as safety and tolerability. How have they been doing?

Well, in the combination with ezetimibe and NEXLIZET, we see about a 40% reduction of LDL and another reduction of this HSCRP and the -- also, like I showed you, we talked about the RDW. In the beginning when your product first came out, there was always a pushback by providers and so forth for cost. And now though, it's really changed and more patients are being approved by their providers without a high co-pay or refusal. So it's become a more commonly, you prescribe medication now since it was about 6 months ago. It's really developed into more of an extensive use by our patients.

Okay. That's really good to hear. We've been working hard to work with managed care groups and make sure their user criteria is aligned with our label. So it's good to hear that you're having very positive experience so that's improved. That's wonderful. So I would love to get your thoughts. I mean you were obviously involved in CLEAR outcomes, and you mentioned some of the data you presented. What's your overall impression of the data from CLEAR outcomes? And has this impacted how you use the products clinically?

It has, for sure. Putting both primary and secondary together in a trial like this is really not commonly done in the past. It was quite intuitive of the company to bring in both primary and secondary risk patients together in this trial to see how well this product does on patients with dyslipidemia and risk. And as you presented in your slide presentation earlier, that primary prevention patients actually did better in the sense of percent reduction, validating, which I mentioned earlier, that initiating therapy for atherosclerosis should start as early as it can. And I think the data and the guidelines you are going to be pushing that down the road, that you don't wait until you have the second event because this is a lifelong disease. It takes decades to develop significant plaque, of course, susceptibility of the vascular disease of development. So the early you start treating their risk factor, I believe, even data are showing this now, the long you're extending the prevention of developing another or first cardiovascular med. So primary prevention is something that we talk about, but we don't actually always practice enough in clinical practice, I think you're going to be seeing more of that.

Okay. Great. Yes, we agree. And I'm glad you commented that you've seen patient access improve, so we continue to get the product to your patients who are in need. Can you comment -- again, when we think about non-statin options, from your perspective in working with your patients, is there a real desire to try oral therapies before injectables?

For sure. For sure. For a majority of patients, it's a priority because, as you know, injecting into your skin is more aggressive and more invasive than just a pill in your mouth and people are used to taking pills regularly since childhood. So these are very complex consequences they have to hurdle to do the shots. Even though the shots that we use PCSK9 inhibitors and so forth, they're very safe in their method of admission, but it's still a complex process. And it raises the price of the therapy, no matter what. An injectable therapy is going to be costly for a patient. And some patients cannot really combine with that need to have that done once a week or once every 2 weeks depending what kind of dosing is being requested for this. So I think the pill is definitely -- oral medications definitely outweigh the injections.

Okay. Okay. So one last question, I think, then we'll open it up to the audience to see what questions. But Dr. Moriarty, I am interested in hearing your perspective on some novel mechanisms or routes of administration that are currently in development to lower LDL cholesterol, namely CTP inhibition as well as oral PCSK9. So as someone who's been involved in many, many years in working with companies, testing these products in your patients, love to hear your perspective.

Well, starting off, let's say, what the PCSK9 inhibitors. I was involved in many of the ODYSSEY OUTCOME trials. I was first author of 2 of the trial studies, the Odyssey alternatives, as I mentioned earlier, Odyssey Escape, which was using [Erlotinib] in patients on apheresis. I also did a similar trial with Amgen with their Repatha and other trials with Amgen, still doing some more now. And they're a great drug for lowering LDL by 60%, 70%. But unfortunately, the outcome data, be it the ODYSSEY outcome or the Amgen FOURIER trial, which were the 2 major Phase III trials, if you looked at the data, the patients who had the significant clinical cardiovascular event, which there was a percentage, which was similar, by the way, to the CLEAR trial. Even though your LDL reduction was almost 1/3 of what was shown in the PCSK9 trials, the event rate was about the same and the absolute risk reduction was about the same. But they found in the Odyssey outcome in the FOURIER trial, if you had a normal Lp(a), your event reduction was not significant. If your LP(a) was very high and the PCSK9s have a modest effect on LP(a), that showed a significant benefit of cardiovascular event reduction if the LP(a) was high. And as I mentioned earlier, the HSCRP and RDW levels are not changed like they are with your drug with PCSK9-inhibitor so for some reason, which is very interesting and we don't know why. If you're lowering LDL by 60%, you can't lower inflammatory markers on top of that, it's very strange. And we don't understand that lack of mechanism. So I kind of readdress my usage of the PCSK9 inhibitors in the recent year or so based on this knowledge that if their LP(a) is not elevated, that even lowering in LDL by 60% might not have as much bang for the buck as you expect. Now that needs all still to be worked out, but the data is there to show you. Now with the CETP inhibitors, I've been associated with them over the years. And they are an incredible class of drug effects in the sense of lipids raising HDL 100%. And now with these newer versions, they can lower LDL and LPLA quite dramatically. But I'm still -- and there's outcomes that's going on now, as you know. But I'm still kind of worried about the effect on HDL. It might raise the HDL, but it looks like the HDL raise is a kind of a dysfunctional HDL because it lacks increased particle number, which has been shown to be quite much associated with HDL functionality. So the jury is still out from CETP inhibitors. Hopefully, the newer versions that are under investigation that lower LDL [indiscernible] more aggressively than the other ones might counteract the negative effect it has in HDL, and result in outcome data that's positive in the sense of reducing cardiovascular events. So hopefully, these studies will be coming out with positive results in the near future. Okay. Well, thank you. Sheldon, operator, I think we're good to change it over to the open portion?

[Operator Instructions] Our first question comes from the line of Dennis Ding of Jefferies.

It's Georgia on for Dennis. We wanted to understand in more detail about what proportion of your patients are you prescribing bem currently? And where does that ultimately go? What's preventing you from using bem more frequently?

That's for you, Dr. Moriarty.