Esperion Therapeutics, Inc. (ESPR) Q2 2017 Earnings Report, Transcript and Summary

Good morning, ladies and gentlemen, and welcome to the Esperion Bempedoic Acid Franchise Development Program Updates and Second Quarter 2017 Conference Call and Webcast. [Operator Instructions] I would now like to introduce your host for today's conference, Ms. Mindy Lowe, with Esperion. You may begin.

Thank you, Takia. Hello, everyone, and welcome to the Esperion Bempedoic Acid Franchise Development Program Updates and Second Quarter 2017 Financial Results Call. I'm Mindy Lowe from Esperion, and with me today are Tim Mayleben, our President and CEO; Dr. Mary McGowan, Chief Medical Officer; Marianne Andreach, Senior Vice President of Product Planning; and Rick Bartram, Vice President of Finance. I'd like to remind the 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 the company's 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 company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's press releases and the company's SEC filings. The content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, August 8, 2017. Esperion undertakes 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 is being recorded and archived. We issued 2 press releases earlier today detailing the content of today's call. Copies can be found at esperion.com within the Investors & Media section. We'll begin with prepared comments from our team and then open the call to your questions. Following today's call, the lipid management team will be available for any follow-up questions. Please e-mail me at mlowe@esperion.com, and we will schedule 15 minutes for you to speak with the team. Now I'd like to turn the call over to Esperion's President and CEO, Tim Mayleben. Tim?

Thank you, Mindy. Good morning, everyone, thank you for joining us today. This morning, we are excited to provide you with enrollment updates from our 3 global pivotal Phase III LDL-cholesterol lowering studies, clear expectations on when to expect top-line results from each of these studies, which we'll start reporting out in the second quarter of 2018 and the resulting acceleration and the expected timing of our 2 NDA submissions. Second, top-line results from the Phase II -038 clinical study of the bempedoic acid/ezetimibe combination added on to atorvastatin 20 milligrams or our triplet oral therapy study. And finally, we'll review our second quarter 2017 financial results. I'd like to begin by saying that I'm very pleased with the progress made by our lipid management team to enroll patients in our global pivotal Phase III clinical studies for bempedoic acid. This is outlined on Slide 4 for those of you that are following along via the webcast. Because of our team's diligence and commitment, I'm happy to report that we are now on track to complete patient enrollment for all three of our LDL-cholesterol lowering efficacy studies this quarter. Top-line results from all of our pivotal Phase III studies will report out in the second and third quarters of next year, 2018. As we outlined in the earnings press release issued earlier today, we will report top-line results from studies 1, 3 and 4 by the second quarter of 2018, while top-line results from study 2, our largest pivotal Phase III LDL-cholesterol lowering efficacy study, are expected by the third quarter of 2018. Perhaps, most importantly, our team's efforts have put us in a position to accelerate the timing for submitting our new drug applications, or NDAs, for both the bempedoic acid/ezetimibe combination pill and bempedoic acid by one quarter, now expected by Q1 2019, rather than the first half of 2019. Moving on to Slide 5. I want to provide you with the regulatory or remind you of the regulatory pathway to approval for both the bempedoic acid/ezetimibe combination pill and bempedoic acid. We have confirmed regulatory pathways to approval for both drugs and this slides look familiar to all of you. The only difference from previous versions that I'll highlight is that we are now on track to submit our two new drug applications to FDA for an LDL-cholesterol lowering indication for both the bempedoic acid/ezetimibe combination pill and bempedoic acid by the first quarter of 2019. Again, this is three months earlier than our previous guidance. Let's turn now to the highly anticipated top-line results from the Phase II bempedoic acid/ezetimibe combination plus atorvastatin study known as the -038 study, which we announced earlier this morning. Working with our CRO and accomplished investigators, we enrolled the study very quickly, and we're pleased to provide you the results today. I'll begin with Slide number 7, which summarizes the design of the -038 study. This was a Phase II randomized double-blind placebo-controlled study in 63 patients, evaluating the efficacy, tolerability and safety of a 180 milligrams of bempedoic acid, 10 milligrams of ezetimibe and 20 milligrams of atorvastatin, what we are calling the combo plus statin versus placebo over six weeks. The primary objective of the study assessed the LDL-cholesterol lowering efficacy of the combo plus statin oral therapy versus placebo. Secondary objectives included assessing the tolerability and safety of the combo plus statin oral therapy versus placebo and effects on other risk markers, including hsCRP, non-HDL-C, total cholesterol and ApoB. A total of 63 patients with hypercholesterolemia were washed out of their lipid-regulating therapies and supplements, immediately prior to a run-in period of six weeks, and had untreated baseline LDL-cholesterol levels between 130 and 189 mg per deciliter. 43 patients received the bempedoic acid/ezetimibe combo plus statin therapy. 20 patients received placebo. With that as background, let's move to Slide 8, which summarizes the top-line LDL-cholesterol lowering efficacy results, the primary endpoint of the study. As we highlighted in today's top line results press release, the 038 study met the primary endpoint of greater LDL-cholesterol lowering from baseline with the combo plus atorvastatin with very strong p-values. Patients receiving the combo plus atorvastatin therapy achieved a very robust 64% LDL-cholesterol lowering. The treatment group had a mean baseline LDL-cholesterol level of 154 mg per deciliter and their LDL-cholesterol level was lowered to an incredible 56 mg per deciliter. This is an absolute reduction in LDL-cholesterol of almost 100 milligrams per deciliter. These reductions in LDL-cholesterol occurred within three weeks of initiating therapy and continued throughout the treatment period. I should highlight that our thought leaders commented that the rapid onset of effect seen with the triplet oral therapy is not typically achieved with individual oral LDL-cholesterol lowering small molecule therapies. Let me take a minute to put this 64% reduction in LDL-cholesterol in context for you relative to the well-known data for bempedoic acid and for the combination for the atorvastatin 20 milligrams with ezetimibe. As in clinical practice, we would expect that bempedoic acid would be added on to atorvastatin and ezetimibe, which are, of course, now standard of care oral drugs. We know from the label that the combination of atorvastatin 20 with ezetimibe, known outside the U.S. as Liptruzet, lowers LDL-cholesterol by 54%. So using the mean baseline LDL-cholesterol level of 154 in the study, a 54% reduction would result in an LDL-cholesterol level of 71 mg per deciliter. But the use of the 3 oral therapies in our study resulted in a final achieved LDL-cholesterol level of 56 mg per deciliter, showing that bempedoic acid reduced LDL-cholesterol by an additional 15 milligrams per deciliter or 21%. And this 21% is nicely consistent with our earlier statin add-on studies. For additional context, on Slide 9, we're showing a waterfall plot of the LDL-cholesterol lowering results. Each bar represents an individual patient enrolled in the treatment group of this study. The consistency of the significant 50% or more LDL-cholesterol lowering in each and every patient by an oral therapy is unprecedented, and one of the truly remarkable findings according to the thought leaders who reviewed these results with us. Next on Slide 10, I also want to highlight two other unexpected and important findings. First, 95% of the patients treated with the combo plus atorvastatin achieved LDL-cholesterol lowering of 50% or more. Second, 90% of patients achieved an LDL-cholesterol level of less than 70 mg per deciliter. So the combo plus atorvastatin 20 milligrams demonstrated an amazing ability to get patients to go, whether that's the percent LDL-cholesterol lowering goal or the target LDL-cholesterol level goal. So the use of bempedoic acid, ezetimibe and atorvastatin 20 milligrams together, a triplet oral therapy, if you will, with three distinct, yet complementary mechanisms of action had several unexpected benefits: first, the consistent LDL-cholesterol lowering response across treated patients that could be considered pan-genotypic; second, very strong reductions, very strong reductions in other atherogenic lipids and lipoproteins such as ApoB, especially relative to the 64% reduction in LDL-cholesterol; and finally, getting almost all patients to goal. 90%-plus in each case, either the 50% LDL-cholesterol lowering or the greater than 70 -- oh, I'm sorry, the less than 70 mg per deciliter target level. So let's turn now to Slide 11 and the hsCRP efficacy results. The bar graph shows the hsCRP reduction in the -038 study. Consistent with prior studies, the combo plus atorvastatin demonstrated a reduction of 48% in hsCRP. As you know, hsCRP is an important marker of information in coronary disease. I want to emphasize that bempedoic acid is the only LDL-cholesterol lowering therapy other than a statin to consistently show significant reductions in both LDL-cholesterol and hsCRP. And for context, it's also worth noting that the recent top-line results from the CANTOS CVOT demonstrated for the first time the direct association of significant hsCRP reductions, with reducing the risk of cardiovascular disease. So let's turn now to safety and tolerability demonstrated in the -038 study. Looking at Slide 12 and consistent with prior studies with bempedoic acid, the combo plus atorvastatin was safe and well tolerated in the study. There were no serious adverse events reported in the study and discontinuation rates were very low overall and similar in both groups. On Slide 13, we are showing the key lab values from the -038 study. I want to emphasize there were no CK elevations greater than 5x the upper limit of normal and no ALT/AST elevations greater than 3x the upper limit of normal. This is important because increases in ALTs and ASTs almost always occur within 4 weeks of LDL-cholesterol lowering therapy initiation. Moving on to Slide 14, we highlight muscle-related events. And the bempedoic acid/ezetimibe combination plus atorvastatin was observed to be well tolerated with no differences in muscle-related adverse events and muscle-related discontinuations when compared to placebo. So overall, I can tell you we are enormously pleased with these results. As shown on Slide 15, the -038 study demonstrated what we could only have hoped it would, that is the combination plus atorvastatin 20 milligrams, which is the most prescribed dose of the most prescribed statins, provide a very robust LDL-cholesterol lowering of 64% as a once-daily oral therapy. The bempedoic acid/ezetimibe combination plus atorvastatin also provides truly remarkable hsCRP reductions. Once-daily oral bempedoic acid can be safely and conveniently used with the two most prescribed oral LDL-cholesterol lowering classes, satins and ezetimibe. And the combination of these three convenient complementary oral LDL-cholesterol lowering therapies was very well tolerated in the study. And finally, based on these positive results, we can confidently design, initiate and complete additional combo studies to further round up the profile of the combo pill and explore the market dynamics of combinations of these convenient, cost-effective, once-daily oral LDL-cholesterol lowering therapies. We expect future studies will provide physicians with an even deeper understanding of how best to prescribe the combo pill to achieve LDL-cholesterol lowering goals for their patients, while also achieving the optimal tolerability that has been so elusive with the use of high-intensity statins. And of course, I demonstrate the payers that oral combinations that include bempedoic acid will likely be the most cost-effective means to achieve LDL-cholesterol lowering goals. We plan to announce future, non-registrational clinical studies for the combo pill, plus statins by Q1 of 2018. The results today -- that we announced today reinforce our confidence that the bempedoic acid franchise offers multiple therapeutic options and demonstrates the power of convenient, cost-effective, once-daily oral LDL-cholesterol lowering combinations. Now before I turn the call over to Rick for a review of our second quarter financials, I would just like to briefly highlight on Slide 16 that the CLEAR Outcomes, cardiovascular outcome study continues to initiate sites globally and enroll patients. The study remains on track to be "well underway" at that time of our LDL-cholesterol lowering indication NDA submissions now expected by the first quarter of 2019. As a reminder, patients in CLEAR Outcomes are high-risk cardiovascular disease patients with ASCVD and/or heterozygous FH. However, the background therapy of these patients is different as compared to other recent CVOTs either initiated or completed. The background therapy in our CVOT includes ezetimibe, PCSK9s and, of course, less than the lowest approved daily starting doses of statins. As a result, baseline LDL-cholesterol levels for patients in our study will be much higher, estimated to be at least a 135 milligrams per deciliter. And one other important advantage to note with CLEAR Outcomes. Patients in our CVOT will be in the study significantly longer than other recent studies. An estimated average duration of 3.75 to four years. We anticipate we will announce top-line results from CLEAR Outcomes by 2022, when the study is expected to have accrued 1,437 four-component MACE events, the primary endpoint of the study. We'll continue to provide you annual updates on the progress from this large long-term clinical study each February going forward. So with that, I'd like to turn the call over to Rick, who will review the financial highlights from the second quarter.

Thank you, Tim. As of June 30, 2017, Esperion had approximately $181 million in cash and investment securities and approximately $1.9 million in debt outstanding under our existing credit facility. Based on our current cash position and anticipated future spend, we expect our current cash and investment securities to be sufficient to fund the completion of our global pivotal Phase III programs and operations into early 2019. R&D expenses for the three months ended June 30, 2017, were $38.2 million compared to $9.7 million for the 3 months ended June 30, 2016. The increase in R&D expenses was primarily due to the continued clinical development of bempedoic acid, which includes cost to support the global pivotal Phase III LDL-cholesterol lowering program and the CLEAR Outcomes CVOT as well as future -- further increases in our headcount, along with additional noncash stock-based compensation expense. G&A expenses for the 3 months ended June 30, 2017, were $5.4 million compared to $4.6 million for the 3 months ended June 30, 2016. The increase in G&A expenses was primarily due to cost to support public company operations, increases in our headcount and other costs to support our growth. The net loss for the 3 months ended June 30, 2017, was $43.3 million or $1.92 basic and diluted net loss per share compared to a net loss of $14 million or $0.62 basic and diluted net loss per share in the prior-year comparative period. I'll point out that cash used in operations during the quarter was approximately $26 million compared to the $35 million spent last quarter. And that difference to the net loss for the second quarter includes a significant component of noncash expense such as stock-based compensation and the recognition of expense on costs prepaid during the first quarter. Put simply, since I went over that pretty quickly, and everyone may not have picked it up, our cash spend this quarter was $26 million, much lower than the reported net loss number due to the significant noncash expenses this quarter. We currently have 22.6 million shares of common stock outstanding with another 4.6 million to be issued upon the exercise of options and warrants. Looking forward, we estimate the cash used in operations for the full year 2017, which I'll remind you, is consistent with our prior cash burn guidance, will be approximately $125 million to $135 million. And keep in mind, as I mentioned a few moments ago, we have -- expect to occur approximately $25 million of noncash expenses during the full year 2017. So those expenses primarily consist of stock-based compensation expense, but that'll contribute to our estimated full year net loss of approximately $50 million to $65 million -- $150 million to $165 million. We expect to end 2017 with approximately $105 million to $115 million in cash and investment securities, which is consistent with our prior guidance. And as I mentioned earlier, we continue to expect our current cash and investment securities will be sufficient to fund the completion of our global pivotal Phase III program and carry operations into early 2019. So with that, I'll turn the call back over to Tim for closing remarks.

Thank you, Rick. So before we open the call to your questions, I do want to take a minute to comment on our partnering strategy. So as we've said previously, we've initiated a partnering process for bempedoic acid for the bempedoic acid franchise, and we are evaluating both potential global and regional partners. We strongly believe that the best opportunity to maximize the value of the bempedoic acid franchise is with a large company with the commercial resources to drive broad market penetration, specifically in our target patient populations. Now with full worldwide commercial rights to bempedoic acid and a compelling and growing clinical data set, we believe that we will be able to justify very promising terms. We are not wedded to having a deal done by a certain date, nor are we giving any detailed guidance, and that's been consistent on timing, but we do continue to work constructively with potential partners and this remains, as we said at the beginning of the year, our number one business priority. We are finding that discussions regarding a potential collaboration are advancing well. At the same time, with very positive results like those we announced earlier today, we're feeling more confident than ever regarding our prospects for taking the bempedoic acid franchise through approval. With the cash that we have on the balance sheet, the advanced stage of development of the bempedoic acid franchise and the data from our Phase III program that we will be announcing mid-next year, we're in a position to drive highly favorable terms, and, of course, we'll continue to weigh the benefits and risks of a partnership versus driving initial commercialization on our own. But either way, we will be ready for the launch of the bempedoic acid franchise products by early 2020. So with that, let me briefly review our key upcoming milestones on Slide 18. First, we will initiate and announce the design of the bempedoic acid/ezetimibe combination pill global pivotal Phase III bridging study next quarter. Also later this year, Dr. Brian Ference is going to publish full results from his Mendelian randomization studies, if you recall that genetically validated ATP Citrate Lyase inhibition. We are on track to announce the top-line results from all of our global pivotal Phase III studies of bempedoic acid by the second and third quarters or midyear 2018. Finally, we are now planning to submit NDAs for an LDL-cholesterol lowering indication for both the bempedoic acid/ezetimibe combination pill and bempedoic acid by the first quarter of 2019, a full three months ahead of our previous guidance. The next few months leading up to our Phase III data in 2018 should prove to be very exciting and eventful. So we'll now open the call to your questions. Takia, would you poll for questions, please?

[Operator Instructions] Our first question comes from the line of Michael Yee of Jefferies. Your line is now open.

A couple of quick questions. So, I guess, my question is on the clinical implications and commercial implications for the data. In other words, in a few years, assuming your drug is on the market, how do you see that fit in? Do you see most people on statins? So they want to add the Zetia bempedoic acid combo or is it that they're already on that Zetia already because it will be generic, so they just want to add the monotherapy drug? How do you see that all playing out, realizing PCSK9 and Novartis' CANTOS program will be there? And then just the second question is a follow-up to your partnership comments. I mean, I guess, at some point, by the end of the year, if we don't see anything, is that a time point where it's probably blessed you wait a quarter because all the Phase III data is coming? How should I think about how that plays out by the end of the year?

I'll answer the first question -- or your second question first and then I'll ask Marianne to comment on your first question. So just with regards to the partnering, I think, I would just emphasize something that we said in our prepared comments, which is we're not in any fixed time line. We have, from the beginning, said that our interest is in doing the right partnerships, so we're not necessarily bound by time. But I think we have certainly said throughout the year that coming into 2017 that this would be and has remained our number one business priority. And again, it's very pragmatic. By the end of this year, we'll be theoretically two years from a commercial launch, and we want to be starting our pre-commercial launch activities. We initiated a search for a Chief Commercial Officer last quarter and that's going along well. So we want to have someone in the seat on our side by the end of this year, early next year. And then we'd also like to have our commercial partner lined up by the end of this year, early next year. But again, if we're not going to get the terms that we need for this program, because it is our -- this franchise our one and only. So we're very interested in really maximizing the value from it. So that's going to remain our philosophy on it. Marianne, would you answer the first question?

Sure. Mike, thanks for the question. As we look at the market landscape right now, we see statins being used first, they are the standard of care. They are generic, so they offer a great option for patients and as well as payers and physicians. And now ezetimibe is generic. So as we look at the future marketplace where the bempedoic acid ezetimibe combination and bempedoic acid are going to fit in. And thinking about the data we generated and shared today from the 038 triple therapy study. Ultimately, what we're doing here is offering physicians, patients and payers more options and more flexibility. We can be used with the statins. We've shown those data. We can be used with ezetimibe, we've shown those data. We are now showing that we can be used to be the other two therapies. We, basically, again, are giving more options, so physicians can pursue the therapy that they feel best fits the needs of the patients in front of them. And I think another key piece of this is not just about the LDL-cholesterol lowering efficacy, but about the safety and tolerability, three complementary mechanisms being used together where -- and where the therapies together are all three safe and well tolerated. So physicians have what they're going to be looking for. And the key thing is they have more options. And by providing these data, it gives the option.

Thank you. Our next question comes from the line of Martin Auster of UBS. Your line is now open.

Tim, maybe, just a follow-up to -- on the comments you made about the partnership efforts and then a follow-up to Mike's question earlier. Can you talk a little bit more in detail about kind of what are the key [indiscernible] steps to potential partnership right now? Is the -038 data -- was that something that you think has some resonance with partners that you talk about kind of time frame and having the objective of securing a commercial partner by the end of year or early next year does suggest that you don't really see any other significant derisking that need to take place between now and then to attract the types of partnership terms you bide. Is that the correct interpretation?

Yes, thanks for your question, Marty. It's interesting, the think that I would say at the start is the companies that we're talking to are very large, global companies. And so the way they think about things is varied. But generally, I would say that the primary derisking events have happened. And that, I would just point you back to March of this year, when we reached agreement with the FDA on the regulatory path to approval of the bempedoic acid and then secondly, in June, when we reached agreement with FDA on the 505(b)(2) pathway, the abbreviated pathway to approval for the combo pill of ezetimibe and bempedoic acid. So I think, in large part, what we have seen is our discussions really accelerate with that regulatory clarity, because I think we, and probably you as well, view the U.S. market as the most significant commercial opportunity. And so regulatory clarity in this market, in this part of the global market, is really significant. To your point, the -038 results that we announced this morning, I think what is most interesting to me, this is really, if you remember, we had the -008 results of the combo pill, which was ezetimibe and bempedoic acid back in 2014 and that was on a background of no other therapy. So it's just the combo pill all on its own. We wanted to demonstrate the magnitude of LDL-cholesterol lowering that you could get with the combo pill itself and what we saw was additivity. Bempedoic acid LDL-cholesterol lowering plus ezetimibe LDL-cholesterol lowering resulted in a 48% LDL-cholesterol lowering, nice hsCRP reduction and very safe and well tolerated. And the question that had come up more recently was what would this drug look like on top of our background statin therapy? And could you do it? So, of course, when folks ask us those kinds of questions, whether it's physicians or folks in the investment community, it makes us think about whether this is something that makes sense for us to do. And so when we first started the study, we started talking about it as a triplet oral therapy study. But, of course, as the bempedoic acid/ezetimibe combo pill came in to sharper and clearer focus, we realized that what we had in our hands was really a preview of what we might see in this upcoming pivotal bridging study of the combo pill on top of the background and maximally tolerated statin therapy. And I think another way to think about these results, you asked me about what derisking events. I think another way to look at these results is really a window into what we're likely to see in that combo bridging study, where patients are going to come in to that study on a background of their maximally tolerated statin therapy. Of course, you know 20 milligrams of atorvastatin is a moderate intensity statin. But we've shown, I think, as Marianne has said that whether it's low-intensity statin or high-intensity statin, we're going to get between 20% and 24% incremental LDL-cholesterol lowering. So, I think, again, these results are very consistent with what we've seen before and again provides a nice window into what we're likely to see in that pivotal bridging study that we're going to initiate later this year. So hope that's helpful, Marty. Any follow-on questions you would have?

Thank you. Our next question comes from the line of Thomas Shrader of Stifel. Your line is now open.

This is Alex Schwartz on for Tom Shrader. So just I'm thinking, to get this data into the label, is this trial sufficient? Will you potentially need to conduct another trial? Or could the combo bridging study be sufficient?

I'll defer to Marianne on that question, Alex, but it's an interesting question. Marianne?

Yes. Alex, as we've talked about this study, we've actually described it specifically as being non-registrational. At this point, what we were doing is really exploring what would happen with respect to the combination and atorvastatin 20 milligrams. The next step, as you know, which is the filing -- is the submission of the NDA for the bempedoic acid/ezetimibe combination as well as bempedoic acid by itself. And this study, for us, really is the first step of a series of trials that we would like to conduct to further evaluate, again the flexibility of the combination of bempedoic acid and ezetimibe relative to the various background statins, specifically focusing to start on the most prescribed of those statins and to follow that. Again, this is a Phase II non-registrational study and provides us with the first step. It's something that we're thinking about with respect to where we could go from a regulatory perspective. But right now, from -- we're going to focus on bempedoic acid as well as bempedoic acid/ezetimibe combination, specifically with the trial that Tim had just spoken about that we'll be starting later in the year, which will be the Phase III bridging study for our combination.

Okay, very good. And then I just had one more question about that combination study. You recently initiated PCSK9 inhibitor plus ETC-1002 trial. Just -- what are you hoping to learn -- what are your hoping to learn? And when you anticipate that trial will read out?

Alex, that's actually a very good question. So this has been a very interesting study for us to think about. And again, I mentioned earlier, a lot of the ideas that we get for these non-registrational studies comes from the thought leaders. So in discussions with thought leaders, again there's not an expansive population of patients out there, where you would envision they would need both a PCSK9 and a branded drug like bempedoic acid. But having said that, there are these patients out there that are heterozygous, severe heterozygous FH or homozygous FH and really have difficulty tolerating statins. Again, there is not a huge population, but there's certainly some of them. And I think, again, really being focused on patients, we say, well, those are patients that really have a high unmet need, right? I mean, there is -- they need non-statin oral LDL-cholesterol lowering therapies, they need just about any LDL-cholesterol lowering therapy that they can tolerate. And if they can't tolerate statins, then we feel a certain obligation as drug developers to say, let's make sure physicians have the comfort, the confidence to be able to use a drug like bempedoic acid in combination with an injectable PCSK9. We know the economics are only going to make sense for a very few patients. But having said that, these are truly the most severely ill patients. And again, we feel an obligation to want to provide them with the confidence to be able to prescribe these 2 drugs together. So as it relates to timing, this study will likely read out in the first quarter of 2018. So we would anticipate, obviously, just ahead of the pivotal Phase III readouts, we would have the top-line results from this so-called PCSK9 add-on study.

Our next question comes from the line of Jason Butler of JMP Securities.

First question, just on the rapid onset of action, can you just talk a little bit about how quickly you're seeing a separation with placebo and how that compares with other LDL-C reduction -- reducing drugs?

Yes, so this is Tim. I'll say that if you remember, we have typically seen a pretty rapid onset of effect that is a getting to the full LDL-cholesterol lowering within about four weeks. And that's generally true with statins as well. In this study, as you've heard us say, we first measured LDL-cholesterol levels at three weeks and then again at six weeks. What was striking to the thought leaders was that at three weeks, the full effect of the LDL-cholesterol lowering for all of these patients was seen when we published the bar graph. What you'll see is a straight line down to three weeks and then a straight line across all the way through to the six week end of the study. So it was striking. As I think we said earlier, typically, you don't see that happening that often with or that quickly with an oral drug, of course, you see it with the biologics. But don't typically see it with oral small molecules. And again, we think it probably has to do with, I think, as I say and Marianne said earlier, the complementary nature of these three drugs mechanism of action and also almost this sort of pan-genotypic response that all patients are responding to these 3 drugs together, which is very satisfying, obviously.

And then this is a question about a comment on one of the safety slides. When you saw LFT elevations that were not repeated and confirmed, can you just talk a little bit about the process to repeat and confirm and just to identify them as single elevations? And did you see any imbalances there between drug and placebo or anything unexpected? And then finally, has the way you've assessed, repeated and confirmed LFT elevations been consistent throughout the development program?

I'll answer the last question first, this is stuff we don't change. There are guidelines that we adhere to about how these things are measured and we stick to those, Jason. So you're never going to see, from us, a moving of the yard marker, if you will. But I'll ask Marianne and/or Mary to comment on the first one. Marianne?

I'll start and then Mary, I think it'd be good if you would also weigh in on this. Going back to just something that Tim said, any evaluation of liver function testing is per protocol and the language all the protocols that we've been conducting has been consistent. When an elevation is seen, it automatically triggers a follow-on elevation because you can get in a single increase in either ALT or AST and then bring the patient back and look to see if it's -- if you're able to repeat that increase and it doesn't happen. So to prevent a focus on more spurious increases, that's why if you look at the slide, we talk about these as being repeated and confirmed. So when we look back at the trial and look at what we've seen, there doesn't appear to be any level of imbalance, simply because there really isn't anything to look at with respect to these elevations in LFTs. The most important measure is what we confirmed on the slide is that what FDA and what practicing physicians are most interested in is that AST/ALT greater than 3x upper limit or normal and you go back and within a short period of time, remeasure it and confirm that. Mary, is there anything you'd like to add on to that?

Yes. Thanks, Marianne. And so our standard practice is to get the patients back in as quickly as possible, but we do define that the repeat has to occur within 1 week. And most often, it's even faster than that. And we had not a single patient who had an elevation in ALT or AST had a repeated and confirmed elevation [Indiscernible] stay on the drug.

Our next question comes from the line of Joel Beatty of Citi. Your line is now open.

First question is, is there any possibility for a triple pill incorporating all 3 of these drugs at some point in the future? And if so, what are the steps that are needed to get there? And then a second question is now that we have this additional data and this market combination, could you update us on how you think about what type of sales force would be best for bempedoic acid? And mainly, for example, would it be a sales force focused on cardiologists or is there an opportunity of primary care offices as well?

I'll ask Marianne to comment on the second one and now I just forgot your first question.

A triple pill.

Yes, thank you. So I was thinking very quickly as you were -- as you were asking that question. So, of course, the possibility is intriguing. It's -- I would also say it's pretty enticing as well, when you see data like this from the 038 study, it's very intriguing. And that, of course, stepping outside of the data, you would think about this from a commercial standpoint, what benefit could this confer. And again this data is very fresh. Obviously, I've have been un-blinded to this a very short period of time, so we're just now thinking about the implications of it. But at least, you could be thinking, we are starting to think about the commercial applications of it. And of course, a lot has been made over the last -- a lot of ink has been spilled, if you will, over the last year or two about the so-called high deductible plans that many patients are on. And as a result of those, patients who have a high medicine burden, they're paying multiple co-pays each month. So you could think about the possibility of having a triplet pill that would have the convenience of just one pill a day, and then obviously, a single co-pay. And again, when you think about the LDL-cholesterol lowering that you could achieve with that, it's very intriguing, it's very enticing. But I would pause there and just remind you and everyone, we got a lot on our plate. We have the bempedoic acid program, the Phase III program, which we are right in the midst of and managing to -- to very good effect, and we'll have all of our pivotal Phase III readouts in the middle of next year. Further, we announced, earlier this year, that we've got the doublet pill for the bempedoic acid/ezetimibe combination and Phase III pivotal program there. And we want to be careful about not taking on too much too soon. So we've just started thinking about what the process would be. I think, what we can say for sure or confidently, I don't want to say for sure, but what we can say confidently is the regulatory path to approval would likely be very similar to the doublet pills using the 505(b)(2) pathway. So that is also intriguing. But it's, I think, far too preliminary at this point for us to comment on specific plans. But I would just say in response to your question overall, I would acknowledge that we've certainly started thinking about it more earnestly and just stay tuned. We've got a lot on our plate now, but we're always thinking about lifecycle management for the franchise, the bempedoic acid franchise. And so we'll continue to think about that and talk about it with interested parties and update folks once we've arrived on a plan. So sorry from the long-winded answer, but I thought it was worth a few minutes. Marianne?

Thanks, Tim. Joel, good to talk to you. As we think about the commercial effort to support a launch of bempedoic acid and the bempedoic acid/ezetimibe combination, I think you've heard us say before, our focus initially would be specialist focus. Not only do we want to focus on those physicians out there such as cardiologists, lipidologists like Mary McGowan, our Chief Medical Officer, and other specialists who are high-volume prescribers or lipid-lowering therapies, but also those who are considered to be early adopters because they can help to guide other physicians toward the use of our product. And so as we think about it, we would start with specialists. However, that does not take away the potential role of primary care. We know that was based on just sheer numbers of physicians that they're going to be able to generate a lot of prescriptions for us. But at this point, as we look at it, it would be more sequential in nature, starting with specialists and eventually going to primary care. Actually going back to the comments that Tim had made about partnering and looking to maximize the value of our franchise. That's why we need a partner. You've heard us speak about the fact that we're looking to build our own commercial organization that would be focused on specialists a partner certainly could work with us in co-commercialization to help really get bempedoic acid and bempedoic acid combination in front of the right physicians at the right time.

[Operator Instructions] Our next question comes from the line of Andrew Peters of Deutsche Bank. Your line is now open.

It's Maryana Breitman for Andrew. I was wondering if I can sort of go back a little earlier and ask you about the Zetia and atorvastatin [indiscernible] and how clinically meaningful you think the addition of the bempedoic acid and the benefit that you're seeing from the three combination, like how do you think would clinicians see it?

Yes, yes. No, it's a good question. And I think we have a clinician on the phone with us. So Mary, perhaps, you could respond to that question?

Yes, yes, absolutely, Tim. From my point of view, the results of -038 are nothing short of outstanding. As a practicing lipid specialist, I am totally thrilled to see the degree of LDL reduction, but not only that, the excellent safety and tolerability of the combination of these three oral agents. So there's a little doubt that this degree of LDL reduction, 64%, will allow almost all eligible patients to achieve their LDL goal. So in my clinic, the only patients who might require greater LDL reduction than this combination can provide would be patients with severe heterozygous or homozygous familiar hypercholesterolemia. Those are genetic disorders which are fairly rare and have markedly elevated LDL-cholesterol levels. And so those would be patients that would need the biologics. But from my point of view, and I would say from the point of view of physicians that I practice with, this is outstanding.

And another thing is, Marianne has mentioned that you're thinking about more sort of combos to better understand, I guess, the patient population assume different combos would work better. Are you thinking about evaluating higher doses of statins? And what would be the expected kind of result, if you were to go that route?

Yes, Marianne?

Yes, it's a great question, because we focused on atorvastatin 20 milligrams and then included it in the -038 study because it is the most prescribed statin and dose of all the statins and all the doses here in the U.S. But as we think about additional combinations, we certainly are going to look to explore, potentially, a higher dose of atorvastatin. We could look at rosuvastatin, we could look at the other statins that are commonly utilized. So that we could then capitalize on what physicians are already doing with respect to their prescribing of statins and demonstrate the benefit of the bempedoic acid/ezetimibe combination on top of those. So it's something we're starting to explore now. Going back to something Tim said, we haven't had the data for that long. So as we're continuing to understand the data set that the -038 results have presented to us, it's certainly generating a lot of thinking internally about potential other combinations. So your question is pressing relative to the discussions that we're having.

Thank you. Our next question comes from the line of Jessica Fye of J. P. Morgan. Your line is now open.

This is Ryan on for Jess. Tim, so you've talked about not taking on too much too soon and given sort of you have a couple of options here with your combos. I know you'll give us an update later on, but is there sort of an initial impression given this data, which you would potentially prioritize over the other?

Well, so it's a good question. I think to best respond to it, again, I'm just going to go into speculation mode here with you, Ryan. I think one of the other -- so what's going on in the market right now, let me take a step back and say what's going on in the market right now, that is the lipid-regulating market is, of course, ezetimibe and Crestor or rosuvastatin went generic here over the last year. So for all intents and purposes, now all of the popular most prescribed LDL-cholesterol lowering therapies that are standard of care, are genetic now. So now what we're seeing is, believe it or not, is -- we're seeing history repeat itself, that is, when the LDL-cholesterol lowering therapies were branded, Lipitor was the most prescribed statin and it generated the most revenue. And we're seeing that same dynamic repeat itself now that all of the statins are generic. Lipitor, atorvastatin is really just the greatest volume of prescriptions is going to Lipitor, atorvastatin. So what does that mean? so the implications, I think, as Marianne said earlier, for this triplet therapy is that we used 20 milligrams in the study because it's the most prescribed dose or the most prescribed statin. And what that has done now, I think, when folks have asked us, for example, historically, about other combination pills, we've -- or other combination tablets, we've said Gee, we wouldn't combine bempedoic acid with a statin because there's 24 different doses of different statins. But what has happened over the last couple of years now is really, this move of atorvastatin to become the most prescribed generic statin. So that has stimulated us to be thinking about combining our drug, bempedoic acid, with the most prescribed statin, perhaps 20 milligrams of Lipitor to put a doublet together of the atorvastatin and bempedoic acid. So when I say we've got a lot on our plate, we've got a lot on our plate from the development standpoint, but we've got a lot on our plate from a lifecycle management standpoint as well that we could conceive now of putting together a doublet pill that would be atorvastatin-based with bempedoic acid, why because that is clearly one of the biggest -- largest volume of prescriptions attributable to atorvastatin. So in addition to thinking about this potential triplet pill, we're also thinking about a combination with statin. And again these are just part of our lifecycle management concepts at this point. We're not announcing any development plans at this stage. But give us some time and we'll have much more thoughtful and planned out responses for you on that.

And sticking with the triplet data, you highlighted the rapid sort of onset of effect and maybe to follow up on an earlier question, I mean, how would you think about the separation of the triple versus a Zetia combo? And then, can you also remind me of the decision to run the triple versus placebo versus an active control as well?

Sure. So with respect to your second question, this was our initial study of the combo plus statin, and we said at the time that we announced the study that it was the first of what we would expect to be many triplet therapy studies. And the decision at that time is -- was simply to do a very simple design, very simple design study with a placebo-controlled. But I think as you look at, for example, this -053 bridging study, the pivotal study that we're doing with the combo pill, that will actually have multiple arms. So it will have active control arms. And then similarly, as we think about additional Phase II non-registrational studies, we also anticipate that we will have active controls. It's too soon for us to tell you exactly what those study designs will look like, but as I said, we expect to announce the next one or two studies that we'll be doing in this theme early next year. And we'll look to announce and initiative those studies in the first quarter of next year.

And I guess my last question is this. I appreciate you laying out the math for us and putting the Zetia combo data into context. But I may have missed this, but if we're assuming like a 15 milligram per deciliter decline, if you take that over the baseline of 150, I got to about 10%. But maybe you can walk me back through the 20% you're trying to get to?

Yes, so and again, we didn't pioneer this or make up a new way of analyzing this. If you go back, for example and you look at how the IMPROVE-IT results were reported, the reduction in LDL-cholesterol of Vytorin versus simvastatin was reported out based on the achieved baseline post the simvastatin vis-à-vis the LDL-cholesterol lowering achieved with simvastatin. So again, we're not pioneering any new way of analyzing the data. So in this case, again, we didn't have separate arms for each of atorvastatin 20 milligrams and ezetimibe and bempedoic acid. But what we do know is that we have a label that has been published for the atorvastatin ezetimibe combo, it's known as Liptruzet ex U.S., and we know from the label that, that gets a 54% LDL-cholesterol lowering. So if we take the 154 baseline, starting baseline and multiply by 54%, then we end up with a 71 achieved, 71 mg per deciliter new baseline, if you will. So if the patient had started on Liptruzet, they would, again, theoretically, get down to the 71 mg per deciliter. But the actual achieved baseline or -- I'm sorry, the actual achieved level of LDL-cholesterol was 56. So 56 from the 71 results in that 15 mg per deciliter. And the 15 mg per deciliter divided into that 71 achieved baseline, if you will, results in that 21%, approximately 21% LDL-cholesterol lowering. Does that math make sense? And like I said, go back and check the math, if you will, by looking to IMPROVE-IT. Like I said, we were not looking to pioneer a new method of reporting results there.

Our next question comes from the line of Chad Messer of Needham & Company. Your line is now open.

Let me add my congratulations not only on the good triple data, but also on the execution with the time lines for NDA filing being moved up. Obviously it usually goes the other way, so it's always good to see. Obviously covered a lot of ground here, but if we could -- could we just check back in on your current thoughts on statin intolerance and a couple aspects of this here? Obviously, with the popularity of Lipitor and statins, this is a larger and huge part of the market, but what are your current thoughts on the market opportunity with statin intolerance and the best way to address that? And then the FDA has historically been kind of reticent to consider that as something for a label, but we've had a lot of new data for them to kind of chew on over the last year or two. Just wondering if there's anything you've -- you're hearing from them to -- that might indicate that their thoughts are evolving on that?

Yes, Chad, that is a very pressing question. So the first thing that I would say about statin intolerance is to remind you and everybody who's still on the call, to -- that patients in our study are hypercholesterolemia patients. We sort of short cut it by saying that if they're statin intolerant patients, but their disease is hypercholesterolemia and ASCVD and heterozygous FH. That's their disease state. They have really elevated LDL-cholesterol levels. It's resulting in atherosclerotic disease for them and that has put them at increased risk of cardiovascular disease. When we short cut it by calling them statin intolerant, what we're really describing and this is insight that we've gained from our interactions with the thought leaders, but also with FDA over the past 1.5 years is that it really defines their background therapy. So a statin intolerant patient is, again, is no different than any other hypercholesterolemic patient, except that they can't tolerate the medicine that is supposed to be able to help them, which is a statin in most cases. So our thinking has evolved about the statin intolerant patient population that, let's not forget that the condition that we're treating for them is not their statin intolerance, the condition that we're treating is their elevated LDL-cholesterol level. And so that hasn't changed the numbers. There are still an estimated 3.5 million to 4 million patients here in the U.S. or 10% of the patients who are on LDL-cholesterol lowering therapies who can't or won't take statins. And so they are not benefiting from statins. So the numbers are still there. The way we've described them more recently has changed in the sense that we're saying, hey, don't forget that these are hypercholesterolemia patients, they're patients with elevated LDL-cholesterol levels, they are patients that have ASCVD and heterozygous FH genetic disorders. But what really complicates their treatment paradigm is that they can't or won't take a statin and that's why we've been pioneering this idea that for patients who can't or won't take a statin, an oral LDL-cholesterol lowering therapy like bempedoic acid or the combo pill, ezetimibe, another non-statin LDL-cholesterol lowering therapy in combination with our drug could really, for the first time, achieve what we think of as statin-like levels of LDL-cholesterol lowering in a non-statin form and provide these patients with something they have not been able to gain access to before which is a cost-effective, convenient, non-statin, once-daily oral therapy that really gives them a 50% LDL-cholesterol lowering, which, like I said, is not available to them today, unless they're willing and able to get an ejection from one of these expensive biologics. So hope that's helpful for you, Chad. Any follow-on questions from that?

Thank you. We will now conclude the Q&A portion of the call. As mentioned earlier, please e-mail Mindy Lowe at mlowe@esperion.com to schedule a follow-up call with management if there are any questions from today's discussion. Now I would like to turn the call over to Tim Mayleben for closing remarks.

Thank you, Takia, and I just want to thank everybody for joining our call today. If you're still on the line, thank you for persisting with us this morning. Really appreciate your interest in and support of Esperion, the bempedoic acid franchise and especially, the lipid management team. We wouldn't be here without you and really appreciate your support. So I look forward to continuing to update you on our progress as we complete final development activities for these two oral therapies and prepare our NDA submissions. We'll also continue to explore the market dynamics of this very interesting combo pill added on to maximally tolerated statin therapy. And as we'd like to say, stay tuned. More importantly, we look forward to proving results from the bempedoic acid Phase III program starting in the second quarter of 2018. We remain very tightly focused on developing oral treatment options for the high cardiovascular disease risk patients with elevated LDL-cholesterol who require additional LDL-cholesterol lowering and are seeking cost-effective and convenient oral LDL-cholesterol lowering therapies.

This concludes today's conference call for Esperion Therapeutics. You may now disconnect.