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

Good day, and thank you for standing by. Welcome to the Clear Outcomes Data Shareholder Analyst Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Tiffany Aldrich, Associate Director, Corporate Communications. Please go ahead.

Good morning, and welcome to Esperion's company update conference call. I'm Tiffany Aldrich, and I'm part of the Corporate Communications team here at Esperion. I want to remind callers that the information discussed on the call today is covered under the safe harbor provisions of the Private Securities Litigation Reform Act. I caution listeners that management will be making forward-looking statements. Actual results could differ materially from those stated or implied by our forward-looking statements due to risks and uncertainties associated with the business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in our March 4 press release and SEC filings. The content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 6, 2023. We undertake no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call and webcast. As a reminder, this conference call and webcast are being recorded and archived. We issued a press release on Saturday, March 4, detailing the content of today's call. A copy can be found at www.esperion.com within the Investors & Media section. We will begin with prepared comments and then open the call for your questions. Following today's call, the team will be available for follow-up questions. Please e-mail [email protected] to schedule time to speak with the team. I'll now turn the call over to Sheldon Koenig, President and CEO. Sheldon?

Great. Thank you, Tiffany, and Good morning, everybody. We're coming to you live from the American College of Cardiology here in New Orleans. This is the last day of the meeting. It's been a really super exciting week here or weekend, I should say, for Esperion as we presented the long-awaited CLEAR Outcomes study, and we're very excited about it. So just from an agenda perspective, I'll do my remarks, and then we'll get into the CLEAR Outcomes data. We are very happy and pleased today to have Dr. Steve Nissen with us. Thank you, Steve. And by the way, this is live, these are not prepared remarks, but we will be going through a series of slides. We'll speak to the importance of CVOT, what it means and bempedoic acid. We'll give a commercial update, and then we'll have some slides related to our financial guidance. Attached is our speaker profile. And if we could go to the next slide. So CLEAR Outcomes is definitely a game changer for Esperion. Not only have we been saying this, but we've also heard many physicians at the American College of Cardiology say as well, again, very exciting results of which Dr. Nissen will go into deeper. I know that even our representatives have been receiving phone calls, et cetera, from physicians looking forward to speak to them. But be reminded that, of course, we will be filing this indication -- 4 indications, later, JoAnne will cover that. Our representatives aren't able to speak to the data, but we've had conversations ourselves with many physicians, et cetera. So again, a lot of excitement, a lot of coverage, et cetera. We have a unique and successful outcome study in a very large therapeutic category, and CLEAR Outcomes really helps again reiterate and demonstrate the benefits of bempedoic acid, the active ingredient in NEXLETOL and NEXLIZET. Another reason of our 3-step plan to really make these products a game changer is that now with Outcomes, we are poised for a major inflection in sales and prescriptions, and we are targeting blockbuster status in this very large market. Our third step or building block, if you will, is based on the robustness of the CLEAR Outcomes data. We believe we will be entitled to receive $300 million in milestone payments from collaborative partners upon inclusion of cardiovascular risk reduction in our European label and up to $140 million upon other regulatory milestones. This is very important for us. It's the first time we've actually reiterated the exact dollar amount, if you will. So I will now turn it over to Dr. JoAnne Foody, and she'll speak to what's next.

Thank you, Sheldon, and Good morning. And I'd just like to provide some context as we think about where CLEAR Outcomes fit relative to the entirety of the LDL lowering field and cardiovascular outcome risk reduction. Let me reiterate that bempedoic acid contained in NEXLETOL and NEXLIZET allows us to have the first non-statin lipid-lowering therapy with a positive cardiovascular outcome study in this space. This is a rarity. You can see here that in the statin era, of course, there were a myriad of cardiovascular outcome studies that demonstrated the benefits of LDL lowering in a broad range of patients. However, multiple agents over the last several decades have been tried to be brought to market and many have failed shown here in red. Since statins, we only have 3 therapies that have been approved in classes, PCSK9, ezetimibe and now bempedoic acid for LDL-specific lowering. When we think about CLEAR Outcomes, we recognize that this is a real game changer, that this is a landmark trial, first of its kind, unprecedented in its scope, assessing the ability of bempedoic acid to improve outcomes in individuals unable to maximize or tolerate a statin. It's focused on a significant underserved population unable to have their LDL addressed with current therapy, conducted in over 14,000 patients in 32 countries, inclusive of 50% women: a real landmark. Let me also remind you that the study included 17% Hispanics, again, demonstrating a unique diverse population. The primary endpoint, as Dr. Nissen will discuss, was MACE-4 and a hierarchy of secondary endpoints. But again, the uniqueness of this study, the population it studied in both primary and secondary prevention and the diversity of the study, all continue to emphasize its uniqueness. This isn't the only study that has assessed the important impact of bempedoic acid and outcomes including LDL reduction and now cardiovascular outcomes. The CLEAR program has now included over 60,000 patients across more than 30 countries and has the largest integrated scientifically rigorous program to establish bempedoic acid as the new standard of care. This being said, our data from CLEAR Outcomes drives a meaningful and significant label expansion and that potential. We now know based on this, that we are poised to benefit many more patients through our therapy. Today, we are indicated for a small subset of patients that have ASCVD, heterozygous FH on a maximally tolerated statin unable to meet their goal. After CLEAR Outcomes and with our anticipated filings, we anticipate a very broad expanded label that will be statin-like in its language to reduce the risk of cardiovascular events in patients with established cardiovascular disease and importantly and differentiated, those at high risk for cardiovascular disease. After the data are considered, we then will remove maximally tolerated statin therapy and as I've mentioned, expand to a broad primary and secondary population, which has only otherwise been addressed in labels for statin. We believe that, based on the robustness of the data, that our products and therapies are optimized to address significant unmet medical needs. While we appreciate that statins remain the first-line therapy to reduce major adverse cardiovascular events, set lower dose statins and withdrawal from these therapies are associated with increased risk. We believe that there is significant number of patients globally, upwards of 30% of patients who are unable to tolerate or maximize statin to reach their recommended doses of statins and that NEXLETOL and NEXLIZET provide a clear option for the millions of patients. We are thrilled to have the scientific community and the premier journal in the world, The New England Journal, provide an overview of our study. In addition to the main paper, we have had positive editorial regarding the utilization of our therapies in the prevention of cardiovascular disease as well as another editorial in The New England Journal, covering the benefits of this pathway. I'd now like to turn it over to Dr. Steven Nissen, the Principal Investigator Chair of our CLEAR Outcomes study, to review the data in detail.

Good morning, everybody, and let me just say that I almost never do this. I have a personal sort of firewall between the scientific work that we do and the financial community. However, given the fact that we spent many years doing this trial that the results are really interesting, I agreed to give you my interpretation of the findings because I think it's important for everybody to understand what we did and did not do here. So this study, CLEAR Outcomes, was designed a long time ago. It takes quite a while to get done these kinds of outcome trials, particularly to get it done in the middle of the worst pandemic in our lifetime. So we enrolled patients that had very well-documented statin intolerance. They had an adverse effect that started or increased during statin therapy and resolved or improved after the therapy was discontinued. We wanted them to be intolerant to at least 2 statins or 1 statin if they were unwilling to attempt the second statin or advised by a physician not to attempt a second statin. They could, however, take very low doses of statin therapy below the lowest approved dose. We deliberately enrolled both high-risk primary prevention and secondary prevention. We have not actually seen a trial with LDL-lowering therapy that included primary prevention patients for about 15 years. We had to have an LDL of greater than 100 milligrams per deciliter. They were randomized 1:1 to bempedoic acid or matching placebo. Like all contemporary trials, this trial was event-driven. So we had to have 1,620 primary 4-component events and at least 810 3-component MACE events and at least 24 months of follow-up. Next slide, please. Statistically, it's very important to understand that we used a hierarchical testing procedure. This is important because with this procedure, if we are successful on the 4-component MACE, we can then test sequentially each of these other endpoints. And as long as there is a statistically significant p-value, we can move to the next endpoint in the hierarchy. What that means is that we have very rigorous data on more than just a composite endpoint. We have data that meets very high standards on all of these other endpoints such as myocardial infarction and coronary revascularization. Next slide, please. We enrolled almost 14,000 patients at 1,250 sites in 32 countries: truly a global effort. We started enrolling in December 2016. We had a median follow-up of 40.6 months. I am extraordinarily proud and pleased that despite the pandemic, we had complete assessment for the primary endpoint in 95.3% of patients and vital status in 99.4% of patients. We did indeed achieve the number of requisite events a little bit higher than we needed. We had 1,746 against 4-component MACE and quite amazingly, 1,238 3-component MACE events, which we needed 810, and we exceeded that significantly. This gives us a lot of statistical power. Next slide, please. We are also really pleased that we were able to enroll 48% women. There's been a huge push by the medical community and the regulators to have a gender balance in clinical trials, and we got there. These were very difficult-to-treat patients. They had LDL cholesterols that were high, 139. They -- we had 30% primary prevention and 70% secondary prevention and about almost half had diabetes. Next slide, please. Now it's important to understand this slide. We specified that we would measure LDL reduction at 6 months. And the reason we do that is that's when we know we have high adherence, very little cross-ins in the placebo group. And it gives us a measure of the effectiveness of the drug that we are testing. You will also see that while the bempedoic acid group did, in fact, maintain the LDL reduction, the placebo group gets a lower and lower LDL. And that's -- this is not a mystery. There were a lot of cross-ins to other therapies, including PCSK9 inhibitors in the placebo group. So that narrows the difference between these 2 treatment groups. It's obviously more difficult to achieve a positive outcome when you have narrower differences, and that's exactly what happened here. The other thing that we saw, very importantly, is anti-inflammatory effects of bempedoic acid, a more than 20% reduction in C-reactive protein, and we will have more to say about that later about the extent to which this drove the favorable outcomes. Next slide, please. So here is the key outcomes. So please understand that each of these outcomes I'm going to show you retains statistical significance as long as there is a positive p-value. So the hazard ratio for 4-component MACE was 0.87, very strong p-value, absolute risk reduction was 1.6%, number needed to treat to prevent 1 event over 40 months was 63, which is considered very favorable. 3-component MACE had a hazard ratio of 0.85. That's obviously a little bit better. The p-value was 0.006 and the absolute risk reduction was 1.3%. Next slide, please. Fatal and nonfatal MI had a hazard ratio of 0.77. We were particularly pleased with this finding that clearly, we give LDL-lowering therapy for a variety of outcomes, but myocardial infarction is arguably the most important: a 23% reduction in MI, the p-value was 0.002. Coronary revascularization, the hazard ratio was 0.81, the p-value was 0.001. Again, this is important because coronary revascularization, this includes bypass surgery and stenting, consume a lot of healthcare resources. Even at a place with -- that has very low pricing like the Cleveland Clinic, it's very costly to undergo a bypass operation or a stent procedure. And so this is an important outcome. Next slide, please. Now the next in the hierarchy was fatal and nonfatal stroke. And although the hazard ratio was the same, it was 0.85, because there were fewer strokes, the upper confidence interval is 1.07. So we don't show a p-value because this was the first in the hierarchy where we did not have statistical significance. However, the point estimate of the hazard ratio is very similar to what we saw for the other end points. And then finally, hospitalization for unstable angina had a hazard ratio of 0.66, an upper confidence interval of 0.86. But by the prespecified statistical analysis plan, no p-value is presented because of this hierarchical testing procedure. Next slide, please. Like all LDL-lowering therapies over the last 15 years, there was no effect on mortality. We put this lower in the hierarchy because we didn't expect there to be effect on mortality. Mortality is a late indicator. In the old days, if you had a myocardial infarction, you were likely to die. Now we rush into the cath lab, we open the coronary, people don't die, they may be disabled, they may have heart failure, and they may not die until their second or their third myocardial infarction. And so, like the PCSK9 inhibitors, both of them, there was no effect on cardiovascular death and again, not a surprising outcome. Next slide, please. Now adverse effects, it was important for us to understand whether these patients who had a lot of symptoms on statins would tolerate bempedoic acid. And I'm going to tell you something, sort of, that I didn't say to the audience, but a lot of people told me that this trial was impossible, that these statin-intolerant patients, whatever we gave them, they were going to have adverse effects and not take the drugs. Well, adverse events leading to drug discontinuation, including muscle-related adverse effects were exactly the same between bempedoic acid and placebo. So they did, in fact, tolerate an alternative therapy. They did not have the same complaints. It is very important that there was not an increase in new onset diabetes. Patients who come to see me who don't want to take statins, many of them have read the scientific literature, they know that statins do slightly increase the risk of diabetes. And they say, look, I've got a borderline blood sugar, I'm prediabetic and I'm worried that if I take a statin, I'm going to have diabetes. Now we do give those patient statins. But if I can't convince them to take a statin, I need an alternative. And I was actually quite pleased, and we expected this, that bempedoic acid would not increase blood sugar and it did not. The 2 outcomes of importance here that were -- there was about a 1% absolute increase in gout and a 1% absolute increase in gallstones, cholelithiasis. We did not see a significant increase in tendon rupture, which is currently in the label for bempedoic acid. Next slide, please. Now subgroup analyses is important to understand that subgroup analyses, because they're not adjusted for multiplicity, are considered exploratory, hyposis-generating and not definitive. But you'll notice that every subgroup lines up to the left of 1.0. And that means that there was an improvement in outcomes, even though not all of them are individually statistically significant. Of great importance, we get all kinds of pushback from some naysayers that LDL-lowering therapies don't work very well in women. Well, you see here that the hazard ratio in women was almost exactly the same for 4-component MACE as it was for men. In fact, it was actually just slightly lower, 0.86. So very happy to see that, and we were very pleased because we had a lot of women in the trial. Next slide, please. So there's limitations, obviously. Every trial has limitations. The trial enrolled only patients with documented statin intolerance. Effects in other populations were not studied. The addition of other therapies, including PCSK9 inhibitors, narrowed the LDL differences between bempedoic acid and placebo over time. Why is this important? Because if there had not been all of these cross-ins, we would have expected to see even a lower hazard ratio for the bempedoic acid treatment group. But of course, to be ethical, we have to allow these cross-ins and we did. The pandemic created enormous challenges in achieving complete follow-up in this global trial. What I heard from my colleagues, that they were amazed that we had complete follow-up in 95.3% of patients and vital status in 99.4%. It is really a tribute to our teams that we were able to get this study done in a pandemic with this quality, and that will be very important to the regulators. Next slide, please. So what do we conclude? Well, first of all, bempedoic acid was well tolerated in a mixed population of primary and secondary prevention patients unable or unwilling to take statins. We had a 21.7% lowering of LDL, a 22% lowering of CRP with small increases in gout and cholelithiasis. The primary endpoint, 4-component MACE was reduced 13%; 3-component MACE, 15%; myocardial infarction, 23%; and coronary revascularization, 19%. I told this audience that these findings establish bempedoic acid as an effective approach to reduce major adverse cardiovascular events in statin-intolerant patients. Next slide, please. The article is in The New England Journal of Medicine. Obviously, we're also very pleased. New England Journal of Medicine is very rigorous. We went through 3 review cycles, I mean I think our reviewers and the editors understood the importance and we're really pleased it's there. And it's quite unusual to have 2 editorials with a single article. And the editorials were very supportive. Next slide, please. So I told this audience that this was my kind of final bottom line thought. Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents nocebo effect, that's sort of a fancy way of saying psychosomatic effect or actual intolerance, these high-risk patients need effective alternative therapies. The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins. Next slide, please. Now I showed you the convergence of the LDL curves and what you see is, on the right, the add-ins that occurred in the placebo arm and on the left, the add-ins that occurred in the bempedoic acid arm. And you can see across the board, everything including PCSK9 antibodies, ezetimibe, everything, there was much more drop-in in the placebo arm, and that's why you see the narrowing of the LDL curves over time. Next slide, please. And here, it shows to you graphically, so this is time to add in additional lipid-modifying therapy in the bempedoic acid group, which is in gold and the placebo group in blue. This is obviously -- has an important implication for the interpretation of the hazard ratios that we saw in the trial. Next slide. I think that may be -- yes, one more slide here. The question is, did this drug perform as well as we have seen in statin trials? And so the endpoint for the cholesterol treatment trial is collaborative is what we calculate here. And for that endpoint, the CTTC endpoint, which is kind of a gold standard in many ways, the hazard ratio was 0.85 and the p-value was 0.001. If you then calculate based upon the LDL difference between the 2 treatment arms, you end up with 0.846. You could round that to 0.85, if you'd like. So in fact, bempedoic acid had a statin-like effect for these patients. And it falls exactly where we would expect it to fall based upon prior trials of statins, and I might add, ezetimibe and PCSK9 inhibitors. I think that may be the last -- no, sorry, one more. Here's how the nonstatin LDL-lowering therapies line up. For 3-component MACE, ezetimibe, in many ways, underperformed, it was 0.9 and for nonfatal MI, it was 0.87. The 2 PCSK9 inhibitors, evolocumab was 0.8, alirocumab was actually 0.86, and you then see bempedoic acid falls between the effects seen with evolocumab and alirocumab. For MI, the evolocumab data was very good, 0.73, but we were able to achieve with bempedoic acid, the same hazard ratio, 0.73, better than alirocumab and really a lot better than ezetimibe. So if you kind of look at these nonstatin therapies, bempedoic acid really looks pretty good in comparison to what the other tools we have in our tool chest for treating these patients. Next slide. That is it. And I think I'm going to stick around for a while, and I'll be able to answer questions when this whole presentation is done.

Great. Thank you, Dr. Nissen, thanks for sharing those data. My name is Eric Warren, I'm pleased to be able to give you my commercial perspective. We go to the next slide. I just want to reinforce that we did enter ACC with momentum, demonstrating growth across 2 really important metrics: new retail prescription equivalents as well as new-to-brand prescriptions. These are patients that had never been exposed to our product that were increased from a prescribing perspective. And you can see on the right, 33% increase in these new-to-brand Rxs, the prior -- versus the prior 4 weeks and that we point ending 17 February. Clear Outcomes is definitely a catalyst for exponential growth. We're excited about the data. And not only are we excited, but clinicians are excited about the data that were shared. I want to reinforce 3 key reasons why we will become the next step after statins. First of all, we are the first non-statin LDL-C lowering agent to demonstrate clinical outcome benefit in a combination of high-risk primary prevention as well as secondary prevention patients. That's critical. Second, quantitative market research, research that was conducted after the top line report, validates the significant role NEXLIZET and NEXLETOL will play in clinical practice. And then finally, we are going to scale our commercial efforts to realize the full potential. And again, we're confident and clinicians that we spoke with are confident that NEXLIZET and NEXLETOL is the clear step after statins. Then the next slide. JoAnne provided some context. I want to go into this a little bit deeper about how our positioning will change after CLEAR Outcomes. And the magnitude of the increase in addressable population is pretty significant, the increase that happens by removing 2 of the barriers that we face: one, maximally tolerated statin limitations as well as limitations around the ASCVD patient. If you look at today, in purple, we are playing in a population of ASCVD patients that are on maximally tolerated statins that are not at their LDL-C goal. The messaging that we have is, add NEXLIZET and NEXLETOL to reduce LDL-C. We do not have an outcomes benefit that we're capable of communicating today. Well, that all changes with CLEAR Outcomes. And in a world post CLEAR Outcomes, 2 pretty significant things happened: #1, we add secondary prevention patients regardless of their ability to tolerate statins; #2, we add high-risk primary prevention patients, again, regardless of their ability to tolerate statins. As a result, we go from that add, based upon LDL-C reduction to the clear next step after statins and again, the first non-statin LDL-C lowering therapy to demonstrate an outcomes benefit in a combination of high-risk primary and secondary prevention patients. I just want to spend a minute to go through highlights from the quantitative market research that was conducted that validates the significant role, NEXLIZET and NEXLETOL will have in reinforcing this clear next step after statins, 250 HCPs covering the specialties that are prescribing within this universe, including both prescribers and nonprescribers of NEXLIZET and NEXLETOL, the conjoint analysis, so it allowed us to explore ranges and outcomes across the key primary and secondary endpoints. I want to highlight that the totality of the evidence is what drives exponential share increases. We did some kind of looks to determine what was the impact of changing the MACE-4 relative risk reduction due to the overall share increases. No difference was demonstrated by changing that MACE-4 relative risk reduction between 11%, 13%, 15% and 17%, reinforcing the fact that it's the totality of evidence that drives these significant market share increases. 95% of clinicians now said they would prescribe NEXLIZET and NEXLETOL next after statins. Clinicians will increase their prescribing for patients across that range of primary and secondary prevention, and NEXLIZET and NEXLETOL will take their share across a range of nonstatins with ezetimibe, which is the market-leading non-statin being the #1 source of business. So we're in the midst of scaling the commercial efforts to make sure that NEXLIZET and NEXLETOL are, in fact, the clear next step after statins. We're finishing up HCP segmentation. This will create the basis for field sales force sizing increases. Our promotional messaging is evolving based upon the current label. We're preparing for the CLEAR launch campaign and all of the promotional messages that will accompany these data and the ultimate label change that we'll have. And finally, we are preparing to expand the sales force in advance of the label change. So we feel it's very important to get this expanded team in place by the end of this year to give them a bit of a runway to be able to engage with clinicians prior to the label change. And finally, I just wanted to give you some highlights from our time in New Orleans. The late breaker has generated significant increases in brand awareness, both for NEXLIZET and NEXLETOL as well as for Esperion. We looked at our patient website activity, we saw 1,426% increase versus our average daily activity, and this increase occurred the day of the late breaker. I've put 2 photos and the first photo is of a product theater for NEXLIZET and NEXLETOL. This was on current label standing room only. The second photo is a picture of our booth. Typically, booth traffic is moderate. Our booth traffic was extreme. So incredible amounts of interest, not just from a patient perspective, looking at our products on the website, but from clinicians wanting to learn more about our products and wanting to learn more not only about our products but our company. I'll turn it to BJ.

Thank you, Eric. From a payer perspective, CLEAR Outcomes certainly provides a renewed place in therapy and formulary positioning to revise appropriate utilization criteria for NEXLETOL and NEXLIZET as next for patients using statins or history of statin intolerance and stepped prior to PCSK9 as a nonspecialty oral product with proven outcomes data. We currently have 90% commercial coverage and 34% Medicare coverage, but with CLEAR Outcomes, this data will be pivotal to reduce the burden of PAs to simplify the diagnosis with a common PA. Immediately post ACC, we have 30 clinical engagements with key clinical, medical and formulary decision-makers with the national PBM, downstream key national plans and regional payers. The payers are excited to see the data, especially from a Medicare perspective, where we anticipate rapid uptake for additional formulary coverage in a short period of time from 34% to 70%. From a pharmacoeconomic standpoint, the value proposition, cost effectiveness and budget impact model is compelling. With the CMS' focus on revising the star rating specific to metrics on cardiovascular health and lipid management, we are well poised as next as add-on treatment for high-risk patients already on or previously on maximally tolerated statins who need additional LDL-C lowering to reach treatment goals. And lastly, from a pricing perspective, the current WAC pricing for NEXLETOL and NEXLIZET is linear pricing of $395 versus $590 for 30 days of PCSK9 and $4,800 annually versus $7,200 per PCSK9. And with that, I'll turn it to Ben.

Thank you, BJ. I wanted to provide some color and rationale for our financial plan in 2023. In 2022, we spent a total of $228 million on operating expense, of which $119 million was R&D expense that was primarily deployed against the -- completing the CLEAR Outcomes trial. We're not expecting the same degree of investment that will be required in 2023, though we do expect to have some spend behind our regulatory submissions in the first half of 2023. We intentionally maintained a lean and efficient commercial team in 2022, but we do expect to begin investing in a larger infrastructure towards the end of 2023, working towards the label expansion in 2024, as Eric outlined previously. We therefore anticipate full year 2023 R&D expenses to be between $100 million to $110 million and SG&A expenses to between $125 million to $135 million. Full year 2023 operating expenses are expected to be between approximately $225 million to $245 million. In our March 4th press release, we disclosed that we were expecting to receive $300 million in milestones in 2024 from our European partner, Daiichi Sankyo, upon approval of the updated label language. This is based on the strength of the risk reduction data presented earlier by Dr. Nissen. In addition, we're able to receive up to $140 million from our Japanese partner. These milestones could become available to us as they progress closer to approval and commercialization in Japan. I will now turn it over to Sheldon for a quick wrap up and we'll open up for Q&A.

Great. Thank you, Ben. And again, I want to thank all of you that are on the call as well. So just 3 key takeaways. And again, hopefully, you can hear it in our voice, this has been a really proud weekend for Esperion. I think what's even more important is what we're going to be able to deliver to patients in the next coming months. So the 3 key takeaways are this, and it's what I started with: we have a unique and successful outcomes study that demonstrates the benefits of bempedoic acid; #2, we are poised for a major inflection in sales and prescriptions and are targeting blockbuster status; and #3, as Ben just mentioned, we know that we will be receiving the milestones of 300 and $140 million, respectively. Before I open up to questions, I think what's important is, at Esperion, we've been saying all the things that we would be doing since October of 2021 when we rightsized this organization, and we have done all of those things. And we're not done yet. We've got a lot more to do. We are excited about it, and we're looking forward to continuing to execute. So with that, we'll turn it over to questions. Thank you.

[Operator Instructions] Our first question comes from Dennis Ding with Jefferies.

Maybe just talk about the drop-in impact on placebo and how the LDL kind of trended over time and perhaps a relative read through to the primary endpoint. Basically, could a 13% risk reduction that you saw on these 4, could that be under a capture, meaning it could have been 14% or higher or 15% or higher if placebo performed like historical trials? And to Dr. Nissen, is this a dynamic that doctors will understand?

Yes. Well, first of all, it's a very relevant question. And we can compute it. Obviously, it's hard to predict these things, but I will tell you that the performance was really good considering that drop-in. If the placebo patients had not had excessive drop-in, almost certainly, we would have seen a hazard ratio that was lower. I want to make one more point that everybody here at the ACC gets. FDA wanted us to test bempedoic acid alone because they wanted to know whether bempedoic acid by itself had an effect on cardiovascular outcomes. In practice, we're going to very frequently use the combination product, which contains bempedoic acid plus ezetimibe. That's going to produce a more robust LDL reduction and would certainly -- would be associated with a larger treatment effect. So there's -- we would have loved to have been able to study the combination product, but appropriately, FDA wanted to know what could bempedoic acid do by itself. So 2 things here that I think would enhance the effectiveness. One is less drop-in in a placebo and the ability to use the product that has both ezetimibe and bempedoic acid. So we learned a lot here, but we can extrapolate to what it means in clinical practice.

[Operator Instructions] Our next question comes from Serge Belanger with Needham.

One for the company and one for Dr. Nissen. First for the company, you talked a little bit about how you expect the label to change with this data. Curious if you can get a primary prevention claim as part of the label with this data. And then for Dr. Nissen, we've heard that statin intolerance is a controversial term within the cardiologist community, and you kind of hinted at that in your commentary. Just curious, I guess, what you think about it and what you estimate the percentage of patients that are statin-intolerant whether that is increasing or not?

Serge, this is JoAnne. So I'll answer on behalf of the label. So as we anticipate a label, again, remember that label language is based on the population in which the drug was studied. So we are confident that this drug will have CD reduction in the population studied, that being established, cardiovascular disease and high-risk primary prevention. That is applicable both in the U.S. with the FDA and EMA. And again, confident that because of the population we studied that this would have an indication addressing that broad range and dramatically expanding our label. Steve?

Yes. So you're right, a statin intolerance is a controversial topic. And what I told the audience and I -- and everybody gets this, is that whether it is a psychosomatic disorder or real disorder doesn't matter. I take care of patients as well as doing research. And I have people come in my office and they look me in the eye, and they say -- they've had a couple of myocardial infarctions or even bypass surgery, their LDL is high, and they say, "Dr. Nissen, I've tried a bunch of different statins, I can't walk up the stairs when I take them, I know I need to lower my LDL cholesterol, what can you do for me?" We get these patients referred to us at the Cleveland Clinic all the time. I can't tell you what -- whether it is, in fact, a nocebo effect or the effect of statins. What I can tell you is the scientific literature reports the rates of statin intolerance anywhere between 7% and 29%. I think it's probably somewhere in that middle range. Let me tell you something else that a lot of people don't know. Less than half of the patients that have guideline indications for LDL-lowering are actually being treated to goal. And it's even worse than primary prevention. So there's an enormous unmet medical need. And I think it is going to be important to have more tools in our tool chest, including tools where we can say to patients, "We have very good evidence that if you take this cholesterol-lowering drug, you're not going to have the adverse effects that you experience with statins." So I'm really agnostic about what the causes are. I just know there are an awful lot of people out there that we can potentially help.

[Operator Instructions] Our next question comes from Jason Butler with JMP Securities.

Congrats on a great ACC. I guess it's a couple for Dr. Nissen. You made this point yesterday in the session, but I was hoping you could speak to how readily you think your colleagues will extrapolate the outcomes benefit in CLEAR to patients on top of moderate or high-dose statins or in patients with a lower baseline LDL-C? And then secondly, can you just speak to your thoughts on how important the rapid separation of the MACE curves is in terms of clinical practice?

Yes. Well, first of all, I've done a lot of clinical trials as many of you know. And my colleagues have just been overwhelmingly positive about these results. I mean I've gotten more high-fives from people than I ever expected. And if you haven't seen it, the media coverage of this outcome is just over the top. I mean all the networks, the major news outlets -- somebody texted me the front pages of newspapers in Australia and in the U.K. have this result. So not only do the colleagues get it, that the media get it, and I'm sure patients are going to get it. And there will be an extrapolation. We study the specific population, but in fact, that's what happens in clinical trials. For example, the PCSK9 inhibitors didn't have any primary prevention patients. Now that doesn't mean they aren't being used in primary prevention, but they didn't have any of those patients. So you only get to study a population that you define in a clinical trial, but everybody understands that if a drug works in this population, it's going to work in others. And I might add that, by the way, really pleased that we included both primary and secondary prevention patients here. Now the second question was...

The curves.

Oh, the curves separating. Oh, yes, I made that point in the presentation that within a year, the curves separate, and that's very important because, in general, LDL-lowering therapies underperform when given in the short run. And that's, of course, what was one of the reasons why the PCSK9 inhibitor trials were kind of not very impressive because they weren't short. But what we saw was early benefit. Is it different from statins? I can't tell you that it is, but we didn't have to wait 3 years to see a benefit. I mean that -- those curves separate very early. We did -- the trial was not stopped by our Data Safety and Monitoring Board because we had rules that did not allow them to stop. But probably, we had statistical significance, fairly early in the trial. And I'm glad we took it to completion because you learn so much more when you complete a trial. And I have to take my hat off to these patients who agreed to be in a long-term trial, 14,000 of them, where they knew that they had a very good chance they would get placebo, and they stayed with us through the entire trial, really extraordinary patients.

[Operator Instructions] Our next question comes from Jeff Hung with Morgan Stanley.

This is Katherine, on for Jeff. We have 2. First, you said that the drop-in on the placebo arm was more than you initially expected. Is the proportion that you would have expected? And given that the patient signed statin intolerance confirmation forms, what proportion of patients adding statins would you have anticipated? And then we have a second one for the company. How do you plan to bridge the cash required in 2023 ahead of receiving milestones? And what gives you the confidence that this will not be a significant concern.

So this is Dr. Nissen. We knew that we would have a differential drop-in, but you can't predict how large it's going to be. And I would say that probably what we saw would have been anticipated. And you cannot withhold therapy from the placebo patients. To be ethical here, it's important that we allow it. So it was a burden that we had to overcome in the trial, which we fortunately did. And by the way, I also think that I'm not sure everybody on the call understands that what we really are interested in here is the totality of the data. That's why we had these -- the statistical hierarchy. And so it's important not just to focus on 4-component MACE but also on 3-component MACE, myocardial infarction and coronary revascularization. They are all statistically significant, and they have regulatory and clinical implications that are important to understand. In some trials, they have a primary endpoint and they do not have a hierarchical testing procedure. And so those trials are judged by the primary endpoint alone. I think we were smart to do what we did, and we had the hierarchy right because we got through the first 4 endpoints before we reached 1 where we didn't have statistical significance.

This is Ben. I'll address the cash question here. I appreciate the question. What makes us -- we ended the year with $167 million in cash, milestones obviously come in early 2024. So honestly, we've done a great job managing our burn rate. We continue to manage our burn rate effectively and well. We see that we can extend that for quite a ways. We've had a resounding response to this trial from the medical community, from investors. And frankly, we see our options as completely open coming out of this trial. It's just been a phenomenal response from all parties involved. So we are in the utmost confident feel that we will be fine getting to those milestones.

[Operator Instructions] Our next question comes from Jessica Fye with JPMorgan.

I got a couple of commercial questions for the management team and then last one for Dr. Nissen. But first, on the commercial questions, given the prevalence of hyperlipidemia, I don't think people with high cholesterol are concentrated at centers of excellence. So can you talk about your commercial plans and how you're going to leverage this data into turning the NEXLETOL franchise into a big drug? For example, how many reps are you targeting with the sales force expansion? And related to that, can you recap where NEXLETOL's coverage is today with respect to requiring patients to step through generic Zetia and where you see that looking out, say, a year from now when you have the data on the label? It seems like you generated a better outcomes benefit than Zetia did. And while the product is affordable, it's still not as cheap as a generic. So I'm just trying to understand how that element of the coverage will play out. Last one for Dr. Nissen, you mentioned that you need to have something to offer patients who can't or won't take statins. Is that really where you see NEXLETOL's realm? And how much will you reach for this product to add on, on top of statin?

I'll start it off, Jess. So first of all, as you know, we have a relatively small representative footprint now, somewhere in the 65, 70 range. I'm very proud of the work that this team has done demonstrating 40% growth in net sales last year despite the significant headcount reductions that we made. But with that said, and to your point, we do need to scale this up. I mentioned segmentation is in the midst of reading out. During the segmentation research, we showed clinicians what our new target product profile would look like. That allowed us to determine what the physician profiles are that react the most favorably to the data that we have. We're in the midst of then determining the optimal number of sales representatives to cover these physicians that are more likely to prescribe based upon these new data. So I don't have a number now. I will say this number will not be in the thousands, but it won't be the 70 that we have. And as I mentioned, our goal is to work fairly quickly to start the expansion process and get this team in place in the fourth quarter, so we give them a runway to be optimally effective. I'll turn it over to BJ for the second part.

Jess, just to reiterate, we currently have 90% commercial coverage, 34% Medicare coverage. Of that, commercially covered patients that are preferred, we probably have half of them that require the ezetimibe step now. It's important to note that we have already been successful even prior to CLEAR and the meeting over this weekend to remove the ezetimibe step from several of the plans over the last 3 months. Going into now, post CLEAR, where we really see the opportunity is in the Medicare population, where we have 34% now. The plans that we already have coverage on do not require the ezetimibe step. And we do anticipate getting to that 70% in a very short period of time coverage that will not have the Zetia step as well.

So we have this population, and let me see if I can define what it looks like. There are these large number of people that just won't tolerate statin, won't tolerate any statin. But there is a graded group of patients, some people that will tolerate a very low dose of a statin and we actually pioneered in our clinic, the idea of giving a small dose of a statin 3 days a week. We do this all the time. And then there are people that will take the lowest dose of a statin, 10 milligrams of atorvastatin or 5 milligrams of rosuvastatin, and they're still not at goal. And so what I think we will see here, this is -- obviously, I can't entirely predict. But if you've got somebody that needs a more LDL reduction that can be achieved with ezetimibe and ezetimibe, as I hope you know, has relatively modest effects on LDL cholesterol. We'll go to the combination and the combination product can produce an LDL reduction that's equivalent to about 40 milligrams of simvastatin or 20 milligrams of atorvastatin. And so the undertreated population that have some relative statin intolerance will be sort of the next group that we'll think about. And then finally, there are people that are on maximal statin, may even already be on ezetimibe and they're still not at goal. So what are our choices? Well, we can go to an injectable PCSK9 inhibitor or we can add bempedoic acid, and we can do that as a combination product. So each of those potential patient populations can benefit by additional LDL-lowering and physicians who are savvy recognize that they've got to try to get these patients' LDLs down, whether they're statin-intolerant, relatively statin-intolerant or statin tolerant, but not at goal. So those are all the kind of populations where I think there's going to be some use of this drug.

I will now turn the call back to Sheldon for closing remarks.

Great. Thank you so much. First of all, I want to thank Dr. Steve Nissen, who's sitting to my right for taking the time to do this today. Thank you, Dr. Nissen, I know it's been a very busy ACC for you. I want to thank the team and I also want to thank all of you that called in to listen to this. I know that we still have questions that are stacked up with folks, but unfortunately, we only had an hour today. As Tiffany mentioned, we will be available for questions. I will leave you with this. I've always said that one of our biggest headwind has been awareness, awareness of Esperion and the fact that we have these 2 great products, NEXLETOL and NEXLIZET. Since this meeting at ACC, our awareness has been just -- I don't know how to say anymore, but amazing. To Dr. Nissen's credit, the media coverage that we've received, the folks that have been sending us notes, whether they be text messages, e-mails, voicemails, et cetera, people know about these products now. And again, we plan to maximize these products. We plan to make sure that we're doing something that's also helping patients. So thank you again, and we'll talk to everyone soon. Have a great rest of the week.

This concludes today's conference call. Thank you for participating. You may now disconnect.