We're thrilled to have with us today, Esperion. Speaking on behalf of Esperion who will give you a presentation is our CEO, [Sheldon Koenig. Sheldon?]
Great. Thanks, Jeff. Appreciate it. Good afternoon, everybody, and thank you on behalf of the Esperion Therapeutics. Really appreciate your time here to listen to our story. We have an exciting story, and let's get right to it. Just our forward-looking statement. I'm gonna have to look back because I can't really see the screen. If you don't mind, I'll pay my attention to the screen and pay my attention to you as well. Hopefully we'll have a little bit of time for Q&A afterwards. Just to focus on the Esperion, we've been evolving into really a unique cardiometabolic business. This company started in 2008 by Dr. Roger Newton, and some of you might be familiar with Dr. Newton. He was actually the founder, co-founder of Lipitor.
This was a company that was in Pfizer then spun out of Pfizer. As you know, we've been on our own since. In 2020, we launched two products, NEXLIZET and NEXLETOL. These are two innovative first in class mechanism of action products. NEXLETOL is bempedoic acid. NEXLIZET is bempedoic acid plus ezetimibe, and I'll go into greater detail of them later. Today, as I mentioned, we're really evolving into this global cardiometabolic company. It's not too often that you find a company that's our size that is involved in something, such as cardiovascular. We really want to be the leaders in cardiovascular medicine. Not only the commercialization of these products, but also research and development. We are advancing our CLEAR Outcomes trial. Just as a late breaker, in first quarter, we announced that we are approaching 95% accumulation of our MACE-4 endpoint.
We actually achieved 95% of our MACE-4 endpoint yesterday. We're well on track in completing this study in the time that we've said with the readout of the top line, first quarter 2023, and then the data sometime soon after. We're entering 2022 in a very strong position. As I mentioned, two drugs approved in March of 2020. The CLEAR cardiovascular outcomes trial, we hope to achieve 100% MACE accumulation in the second half of 2022. Again, we just achieved 95%. We're very proud of that. The market is a large market. This is a market that's worth $11.2 billion. A very large market as we continue to progress. We have a very experienced management team.
Two of the folks are here today, Eric Warren, who's our Chief Commercial Officer, and BJ Swartz, who's our Chief Strategy Officer, sitting in the third row. We have compelling global partnerships. Daiichi Sankyo Europe is a partner with us in Europe and also rest of world. In Japan, we have a partnership with Otsuka, who just completed phase II trials of bempedoic acid now entering into phase III. There are significant milestones associated with both of those partnerships upon completion of the CLEAR Outcomes study. In October of 2021, we did a significant restructuring to, one, preserve our cash and also right size the company. You may have seen with our first quarter results, we were able to demonstrate savings of $32 million quarter-over-quarter, as well as consistent growth.
We're well on track on optimizing our cash burn, and we feel we have the cash necessary in order to complete the CLEAR Outcomes study and even to go beyond the CLEAR Outcomes study. This is our management team. It's an experienced management team. We probably have over 200 years of experience combined together. A lot of us have been here in this industry for 30+ years . I think it is important to note that cardiovascular disease is the number one killer among folks today, not only in the U.S. , but the world. It has more annual deaths than all forms of cancer combined. It accounts for one in three deaths in the U.S. and Europe. Not on this slide, cardiovascular disease is also the number one killer of women.
One thing I want to point out is that in the CLEAR outcome study, the enrollment, 50% of the enrollment is actually women. This is very significant. When you look at prior outcome studies, there has not been as many women in studies such as this. There's actually a paper two years ago at AHA regarding the fact that the amount of women that are in this study. We think that'll be a very interesting segment to explore. There's 18.3 million patients still in need to address their LDL cholesterol. If you think about that, if you go all the way back to 1991 with the introduction of lovastatin, which was Mevacor, there are still 18.1 million patients in need. Why is that? Well, patients still have trouble reaching their LDL goals.
80% of these patients at high risk have not received or have not achieved their guideline recommended LDL goals. Close to 9 million patients did not reach their goal despite actually being on the statin. That's because 20% of people who take statins cannot tolerate it. They have myalgia, they have muscle pain, etc. They don't want to be on the drug. One-third of patients discontinue treatment because of this. Again, this harkens back to why is it the number one killer. Close to 10 million patients in the U.S. with high LDL are not on statins at all because of tolerability concerns, won't even try it. Again, if you think about our product, which is really a partner to statins, post CLEAR Outcomes study that actually can be used on its own for these patient types, etc.
I'll go through how the label will evolve once we have the CLEAR Outcomes study. As I mentioned, we introduced these two oral non-statin products in March 2020. Unfortunately, that was the same time as you may recall, COVID actually came upon us. I'm a strong believer that these products never really had their fair opportunity to launch. That hasn't really occurred until January of last year with a new strategy and the right sizing of the organization. I would say actually January of even this year. NEXLETOL, as I mentioned, is bempedoic acid, which in phase III trials showed an 18% reduction in LDL. Let me address your attention to NEXLIZET, which is a combination of bempedoic acid and ezetimibe. This has LDL lowering effects of 38% and sometimes greater.
In real-world experience, in physicians that are writing these drugs, and we have about 12,000 physicians across the U.S. writing these drugs, they have sometimes seen LDL reduction of 50% in using NEXLIZET. We've been very encouraged by physician feedback and what we're seeing in the real world. Just to give you also a flavor, about 60% of writers are primary care physicians, and 40% writers are actually cardiologists. Not only do we have efficacy, but we also have safety established with these two products. Why do we need these drugs? Well, you heard me talk about cardiovascular disease being the number one killer in the U.S. . I've discussed already the fact that we have tolerability issues with statins, et cetera, which are the cornerstone of therapy.
However, there are still patients that need additional therapy, and that's where there's this fit for this, what we call oral non-statin gap. NEXLETOL, as I mentioned, broadly combinable with statins, NEXLIZET also broadly combinable with statins. Ezetimibe, which is a product that I managed some years ago, which is also available from a generic perspective, is available today. Again, keep in mind, NEXLIZET is the combination of bempedoic acid plus ezetimibe. Of course, we have the injectable medications of PCSK9. These are injectables. It's important to note that oral medications, four out of five patients prefer a pill. Patients and physicians would rather take a pill than having to take an injectable.
To just give you an idea of efficacy and some other parameters on how we're differentiated from statins and other products available, I won't go through the entire chart, but what I will address your attention to is, again, the LDL lowering of statins are between 25%-60% high dose, ezetimibe 13%-20%, NEXLIZET 38%. If you look at the PCSK9s, they're between 50%-60% and 52%. What's interesting, though, about NEXLIZET and NEXLETOL, if I can address your attention to the hs-CRP effect, we have a 35% reduction in hs-CRP. This is an inflammation biomarker that we feel is significant. Also not represented on this slide is we also have positive effects on reducing glucose, also blood pressure and weight. We think that's going to be very interesting. We'll have more readout on that data.
These are exploratory endpoints in the CLEAR Outcomes study. It also speaks to further years of development from a pipeline perspective. From a CV outcomes perspective, again, with ezetimibe, we saw a 6% residual risk reduction with the IMPROVE-IT study. Again, this is not in the label for ezetimibe. We expect our label or our results in the second half of 2022, and then we can go and file post that. Praluent and Repatha have a 15% residual risk reduction with both the ODYSSEY Outcomes and FOURIER studies. Leqvio, which is the PCSK9 from Novartis, they have expected outcomes in 2026. I think it's important, though, to differentiate how do these outcome studies differ amongst each other. I'll get to that in just a moment.
I want to remind everybody of what a large market this is. This was a market that in 2011 was, again, growing. We have seen some decrease, but we're starting to see the market with more therapies being introduced and the gap that's out there as it relates to patient needs, the market is actually starting to grow again. We're actually seeing that from a prescription trend perspective, et cetera. In the first quarter of 2022, we actually grew 6.5% from the fourth quarter to the first quarter. What we've stated since October is that we want to demonstrate consistent growth of NEXLIZET and NEXLETOL with the real meaningful inflection point of volume occurring post the CLEAR Outcomes study. We've seen continued growth from a weekly franchise perspective, and we're very impressed by that.
As far as patients staying on the drug, we compare this to other drugs that are used out there today, drugs like Entresto, drugs like XARELTO, et cetera. We have comparison or comparable, I should say, results of patients actually staying on the drug. That's also very encouraging to us. I actually want to transfer to the CLEAR Outcomes study. Dr. JoAnne Foody, who's our Chief Medical Officer, unfortunately, had to leave earlier today, but I'll cover the CLEAR Outcomes study. This is really a study that we believe is unprecedented and also potentially practice-changing. It's really addressing cardiovascular risk reduction, looking at bempedoic acid, a new class of medication, as I mentioned. This is an ATP citrate lyase inhibitor.
Again, we think this is something that is going to be differentiated because we have over 14,000 patients in over 32 countries, and this is the first of a kind ever of a study looking at statin-intolerant patients. These were patients who took at least one statin and could not tolerate it or can only tolerate a certain dose. I talked about the fact that 50% of the studies enrolled is women. What's interesting about the study and reasons to believe this is one of the highest baseline LDL criteria of all studies, and I'll show you a comparison chart next. Patients enrolled in the study started at 139 mg/dL , whereas if you look at other studies that have been conducted, it's usually the enrollment is about 92 mg/dL .
Longer duration of study allows us to actually assess the LDL lowering effects as it relates to CV outcomes, and I'll show you what that duration is. As I mentioned earlier, we think the anti-inflammatory effect and also the glucose lowering effect is going to be something that's going to be very interesting to explore and could also add to the overall efficacy and benefit of the drug. I already mentioned the late breaker. We are approaching 95% MACE accumulation, and we hit that yesterday. Proud to say. I can't say that enough. This is the comparison chart. I won't go through the entire chart, but what I will direct your attention to is median treatment duration. If you look across, what you'll see is FOURIER study, which is, Repatha, was 2.2 years, which is evolocumab. If you look at alirocumab, it's approximately 2.8 years.
Our estimated follow-up time is almost four years, and we think this is something that will be highly differentiated for us. A highly differentiating feature for us moving forward. Our study is powered for a 15% residual risk reduction. But I will say that there was work that was done to give you an idea of how the label will evolve upon approval. Currently today, if we look at our current label, we approximately can address 8 million patients. These are patients who have identified ASCVD, and they're on a maximum tolerated dose of a statin. Once we actually have our CLEAR outcomes data in the label, we'll have a few things that will be different. One, we'll have additional information that talks about that we will reduce the risk of cardiovascular events.
We'll actually have a preventive claim. Two, we won't have ASCVD. Essentially, patients who are suffering from hyperlipidemia or high LDL can absolutely be put on either NEXLIZET or NEXLETOL. It really expands to primary and secondary prevention. Something else that I think is very interesting is that we would also potentially have an indication for statin intolerance. The drug could be used on its own by itself without having to be used with a statin. That's the beauty of these drugs. They can be a partner to any therapy that's out there. We're very encouraged by that. What also is it expands our treatment population by almost 10 million patients to 19 million patients in the U.S. alone. Again, it gives you an idea of how large of a market this is.
This is why you see other large companies, actually larger than us, heading back into cardiovascular medicine. Something that's important is the guidelines. You know, what we'll see upon actual results is inclusion in guidelines. We're actually already included in the AACE guidelines, but this gives you an idea of just looking across the paradigm from extreme risk to low risk, where bempedoic acid could be used in guidelines. Now, this is a subset from the AACE guidelines, and you can see how we're already incorporated. Other large organizations such as AHA and ACC and even the European Society of Cardiology, upon completion of the CLEAR Outcomes study, will start thinking about where do we fit in broader guidelines.
I think it's important to note that there's already individuals thinking today of potentially when would consensus start of thinking about that potential fit of guidelines. This is very important. What I failed to mention is that between guidelines and the outcome study, one of the headwinds that we face today of prior authorization, so physicians writing the drug, prior authorizations will be somewhat diminished. They won't be as high of a hurdle anymore, which will allow for much more easier prescribing as well. To give you an idea of our engagement moving forward from a commercial perspective, this was all launched back in October of last year. It's really leveraging three different pillars, in-person medical communication and sales promotion to targeted cardiologists and endocrinologists and primary care. We're leveraging peer-to-peer networks.
We're actually similar to how this is being recorded. We have physicians who are meeting with physicians over Zoom or other media or using digital technology to actually talk about their experience with NEXLIZET and NEXLETOL. We've actually conducted return on investment analysis to say, does this work? What we have found is that it does work, and that's what has allowed us to have a nice balance between personal promotion and also using digital pathways. This really goes to driving broad awareness by really using digital media. I think one thing that COVID has taught us is that how can we, how can we be more resourceful and how can we leverage the digital tools to get our message across? We have strong intellectual property.
Again, as I mentioned, not only here in the U.S. , but also in Europe and Japan. We have a composition of matter through 2031, and we're also looking for other ways to expand our patents. We feel really good about our intellectual property and not an issue whatsoever. Esperion is a global company. We have global partnerships, strong partnerships with Daiichi Sankyo and also Otsuka. We've already launched in Germany, U.K., and Austria. It's interesting to know that in Germany, the amount of patients on bempedoic acid has already surpassed the total amount of patients on PCSK9s, which have been out there for approximately eight years. As a matter of fact, we have close to 55,000 patients on therapy when looking at both Germany and the U.K. The U.K., we actually just started the launch there.
We have 1,000 patients. We've expanded relationships to the rest of the world with Daiichi Sankyo, so they have other countries, such as Thailand, Korea, Brazil, et cetera. They're actively working there. We have milestones totaling close to $1.2 billion, and that's including milestones as it relates to payments related to the CLEAR Outcome Study, but also royalties that we are paid. Just to give you an idea of one milestone, we can earn up to $300 million worth of a milestone from Daiichi Sankyo upon inclusion of the CLEAR Outcome Study into the European label. With Otsuka, I mentioned their phase II study has actually completed.
With Otsuka, upon the completion of the CLEAR Outcome Study and inclusion in the label, we receive $150 million milestone from them. We have also a growing pipeline, and this is something that we haven't talked much about at Esperion. I talked about the fact that we have effects on glucose lowering, we have effects on blood pressure, we have effect on obesity, and we have effect on inflammation. We have a second-generation ACL program, which we believe is a platform program, and we believe that we can address not only hyperlipidemia and cardiometabolic diseases, but also oncology, NASH, kidney disease, and neurological disorders. We will talk more about this in the second half of 2022, when we plan to have a research and development day. We also have an oral PCSK9 inhibitor.
It's actually more of a platform. This is based upon the allosteric approach, where we can actually look for what we think is the most potent candidate in this area. We're in the process right now of really thinking about how do we get to what's the fastest way to achieving IND. We'll cover this in the second half of the year when we have our research and development day. We're excited about this program. It's not often that you find companies of our size that are not only commercializing products, but we're also invested in research and development. From a cash perspective, we had a significant cash raise in the fourth quarter of last year. Currently, we have $268.5 million in cash and cash equivalents.
I've already covered that we achieved $13.4 million in the first quarter. We believe that we're well-funded, again, to the CLEAR Outcome study and beyond, and we have greater than $1.2 billion potential in milestones from Daiichi Sankyo and Otsuka in our future. The key takeaway here is, again, we have the funds necessary to get to the CLEAR Outcome study and even beyond the CLEAR Outcome study. The CLEAR Outcome study, pardon the pun, is a clear inflection point for this organization. It's a trigger for many milestones and other events for us. Just to give you an idea of the upcoming events. We've discussed before the pipeline asset lead identification. This has to do with our second-generation ACL and our oral PCSK9. Our second half of 2022 is gonna be exciting second half.
We expect, again, the anticipated 100% from our MACE-4 endpoint for CLEAR and potential oral PCSK9 IND submission. As we move into 2023, I'll just address your attention to the first half of 2023, where we believe the top-line results of the CLEAR Outcome Study will be presented at a major medical meeting. The next six months to a year are gonna be a really exciting time for Esperion. To finish, again, Esperion, we're in a very strong position. We have two approved drugs. We continue to stand behind these drugs and grow these drugs to our best ability in anticipation of the readout of the CLEAR Outcome study, which I believe, and many believe, will be practice-changing.
I failed to mention that Steven Nissen, who I think all of you know, a notable clinical trialist, has been here for some time. He's our lead investigator in the CLEAR Outcome Study, and I know he's excited about the results and when the results come out and when he can get behind the stand and actually present those results. We're well-funded and, you know, we're looking forward to sharing those results with all of you, as they come out, and we will continue to keep you updated on anything new, as we continue throughout the year. Again, I just wanna thank everybody. Also want to thank Bank of America for having allowed us to have this opportunity to present to all of you today. Thank you so much. I think we have a couple minutes for questions if anybody has any.
Before the outcome study, how are you seeing as the pandemic kind of evolves to more endemic and maybe some of the, you know, COVID headwinds kind of subside?
Yeah.
Is there an impact that you're seeing, you know, today in the U.S., you know, commercially?
Yeah. You know, not as much. I think it's become almost this is the world that we're living in now. The reason why we made the changes back in October, and I think we are one of the first companies to do that. You know, we dramatically slashed our sales force and we had a lot of people think, "Are you gonna be able to grow?" We had some folks say to us when we actually went into the fourth quarter that, "Wow, okay, we're surprised you're able to grow in the first quarter as well." I think it was really finding that balance between personal promotion and applying these digital tools. We know that these digital tools do work because we've measured them, as I've mentioned. This is the world that we live in.
We're hearing that more offices are opening. There's a large cardiology practice in Atlanta that had been closed for some time that just started opening their doors again. I think it's more just, you know, getting used to this environment and being able to market in this environment. Also, I'll just carry that one step further, Jeff. There's a lot of questions we get too is, did COVID have any effect on the CLEAR Outcomes study and enrollment, capturing data, et cetera? I think we actually have a textbook analysis to say that, no, it didn't. I think someday we have an abstract in our future of how do you conduct studies in a world where you have a potential pandemic going to an endemic. Even from that end, we're okay as well. Feel good about that.
Any other questions? All right. Okay. Well, thank you so much, everybody. Really appreciate your time, and have a great rest of the conference.