Lexicon Pharmaceuticals, Inc. Q4 FY2020 Earnings Call

Good afternoon. My name is Chantal, and I'll be your conference operator today. At this time, I would like to welcome everyone to Lexicon Pharmaceuticals Fourth Quarter 2020 Earnings Call. All lines have been placed on mute to prevent any background noise. After the speakers’ remarks, there will be a question-and-answer session. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Chas Schultz, Executive Director of Corporate Communications and Investor Relations. Thank you.

Thank you, Chantal. Good morning and welcome to the Lexicon Pharmaceuticals fourth quarter 2020 financial conference call. Joining me today are Lonnel Coats, Lexicon's President and Chief Executive Officer; Dr. Praveen Tyle, Lexicon's Executive Vice President of Research and Development; and Jeff Wade, Lexicon's Executive Vice President of Corporate and Administrative Affairs and Chief Financial Officer. Earlier today Lexicon issued a press release, announcing our financial results for the fourth quarter of 2020, which is available on our website at www.lexpharma.com and through our SEC filings. A webcast of this call, along with the slide presentation is available on our website. During this call, we will review the information provided in the release, provide an update on our clinical programs, and then use the remainder of our time to answer your questions. Before we begin, let me remind you that we will be making forward-looking statements, including statements relating to the safety, efficacy and the therapeutic and commercial potential of LX9211, sotagliflozin and other drug candidates. These statements may include characterizations of the expected timing and results of clinical trials of LX9211, sotagliflozin and other drug candidates and the regulatory status and market opportunity for those programs. This call may also contain forward-looking statements relating to our growth and future operating results, discovery and development of our drug candidates, strategic alliances and intellectual property as well as other matters that are not historical facts or information. Various risks may cause our actual results to differ materially from those expressed or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and preclinical studies of LX9211, sotagliflozin, and our other drug candidates; our dependence upon strategic alliances and other third-party relationships; our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities. For a list and a description of the risks and uncertainties that we face, please see the reports we have filed with the Securities and Exchange Commission. I will now turn the call over to Lonnel Coats.

Thank you, Chas. Good afternoon, everyone, and thank you for joining us on the call. We welcome the opportunity to discuss what was a very busy quarter for Lexicon in which we made significant advancements with our two lead compounds, LX9211 and sotagliflozin. During the fourth quarter, we commenced patient enrollment for RELIEF-PHN 1, a Phase 2 clinical study of LX9211 for the treatment of post-herpetic neuralgia. This is our second Phase 2 clinical study for LX9211, which we have initiated in neuropathic pain. Patient enrollment in our other Phase 2 clinical study, RELIEF-DPN-1 in diabetic peripheral neuropathic pain is ongoing. In December, we were very pleased to announce that we received Fast Track designation from the FDA for the development of LX9211 in diabetic peripheral neuropathic pain. This designation is indicative of a serious unmet medical need of this patient population. Also in the fourth quarter, the SOLOIST and SCORED Phase 3 outcome studies of sotagliflozin heart failure, both achieved their primary endpoints. The results of those studies were presented by Dr. Deepak Bhatt during the Late-Breaking Science Session of American Heart Association Scientific Session and were simultaneously published in two separate articles in the New England Journal of Medicine. Based on the strong results from these studies and our subsequent discussions with the FDA, we made the decision to move expeditiously with a New Drug Application for an indication to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent visits for heart failure in adult patients with Type 2 diabetes with either worsening heart failure or additional risk factors for heart failure. We expect the New Drug Application to be filed in the second half of the year. We also closed out the year by raising $70 million in net proceeds from sales of our common stock. Combined with our decision to strengthen our balance sheet by eliminating 95% of our debt, we entered into 2021 in a solid financial position with cash sufficient to fund our planned operations for two years. Looking ahead to 2021, we anticipate a number of events during the year. We expect both of our proof-of-concept studies for LX9211 to read out by the end of the year. We're very enthused by what we have seen from LX9211 in our preclinical and Phase 1 studies and are looking forward to obtaining the Phase 2 results. We plan to share more about the data from these earlier LX9211 studies in the upcoming publications. As I mentioned, we are moving full steam ahead with an NDA filing for sotagliflozin in heart failure, and expect to submit the NDA during the second half of the year. We will need to establish a strategic alliance for sotagliflozin in order to achieve the best long-term value for the asset as well as for millions of people suffering from heart failure worldwide and those business development discussions are moving ahead earnestly. Important data from SOLOIST and SCORED was presented at AHA and in the New England Journal Medicine articles, and there are more analyses ongoing, which we expect to release results and additional publications throughout the year. Now on to Type 1 diabetes. We continue to believe that sotagliflozin demonstrated a positive benefit-risk in the largest Phase 3 development program ever conducted in Type 1 diabetes and that it has the potential to become an important new treatment option as an adjunct to insulin for Type 1 diabetes. We have requested an opportunity for an administrative hearing with the FDA on whether there are grounds for its previous denial of our NDA for Type 1 diabetes, and the FDA issued a public notice of opportunity for hearing just last week. We look forward to continuing these discussions with the FDA. Now let me provide an update on LX9211 which we're developing for neuropathic pain. Despite neuropathic pain affecting millions of people, there remains a high level of unmet need for those suffering from the condition. The current approved therapies are limited by lack of efficacy, compounded by debilitating side effects. As a result, many people turn to opioids to experience some level of relief, which of course, carries its own risks of potential abuse and addiction. We feel that LX9211 through its inhibition of AAK1, independent from the opioid pathway, has the potential to overcome many of the shortcomings of current therapies and could become a welcome new innovation for those suffering from neuropathic pain on a daily basis. I'm going to pause here and turn things over to Dr. Tyle to provide an update on LX9211 and to take you through the data for SOLOIST and SCORED studies, and share a little more on why we think our data may be especially compelling because of sotagliflozin's inhibition of SGLT1.

Thank you, Lonnel. LX9211 is a potent, orally delivered selective small molecule inhibitor of AAK1 which is a pathway we believe may have utility in reducing neuropathic pain, while avoiding the addictive downsides of the opioid pathway. LX9211 was discovered by scientists working within our drug discovery alliance with Bristol-Myers Squibb and we now wholly own all the rights to LX9211, as well as any additional compounds related to AAK1 that we may develop. As Lonnel mentioned earlier, we received Fast Track designation in December 2020 from the FDA for the treatment of diabetic peripheral neuropathic pain. Let me show you some of the preclinical data supporting our view that LX9211 may be beneficial for people suffering from diabetic peripheral neuropathic pain. With diabetic peripheral neuropathic pain, people living with diabetes often develop nerve damage, which causes painful, debilitating symptoms most often in their legs and feet. On this slide, you can see the effect of LX9211 in the gold-standard diabetic peripheral neuropathic pain models in rats. In this model, streptozotocin is used to induce diabetes in rats, and then tests are performed to evaluate the rats’ sensitivity to mechanical allodynia where even a slight touch can cause a painful sensation in rats with diabetes. The brown line represents the rats in which diabetes was induced, while the purple line represents the controlled rats without diabetes and with normal sensitivity to touch. The rats along the brown line are feeling the full effect of neuropathic pain from their diabetes, and they feel pain with any type of touch as shown by 0% inhibition of mechanical allodynia. The rats along the purple line are not feeling any effect of neuropathic pain or sensitivity to touch as shown by 100% inhibition of mechanical allodynia. The lines in between these two extremes show the effect of LX9211 on the diabetic rats. As you can see, there is a clear dose response to LX9211 that enables those diabetic rats to tolerate a significantly higher degree of touch without pain at the 1-milligram and 3-milligram per kilogram levels. By way of comparison, in the same experiment, gabapentin was administered at 100-milligram per kilogram and resulted in a similar response as the 1 milligram and 3 milligram per kilogram levels of LX9211. So we were able to achieve a similar level of efficacy at a much lower dose with LX9211. More importantly, at this level of dosing, we saw no motor impairment in the rats and no impairment of performance in the cognition model, which are the two significant side effects of gabapentin. In addition to DPNP pre-clinical studies, we also studied LX9211 in a preclinical rat model for post-herpetic neuralgia, which is the focus of our other Phase 2 proof-of-concept clinical study. In this model, the varicella zoster virus, which causes shingles, is introduced to the rats. The rats are nocturnal by nature and prefer to stay in the dark, usually only entering the light when under duress. In this model, we looked at the time that rats spent in the dark versus the light over five-minute intervals or 300 seconds when stimulated with a 60 gram filament every 15 seconds. On this slide we had a head-to-head test of LX9211 at 30 milligrams per kilogram versus gabapentin at 100 milligrams per kilogram. On the left, you can see the results on a single dose of LX9211 and gabapentin with both arms providing a statistically significant improvement in the time spent in the dark as compared to untreated rats represented by the dotted line. In the multiple dose administration on the right involving seven daily doses of LX9211 and gabapentin, we saw further separation. When comparing gabapentin-treated to LX9211-treated rats, the pain response was significantly better in the LX9211-treated rats. Also, as in the case of the DPNP model, with LX9211 in these doses, we saw no motor impairment in the rats and no impairment of performance in the cognition model, which are two significant side effects of gabapentin. Our preclinical data for LX9211 has demonstrated excellent CNS penetration and reductions in pain behavior in animal models of neuropathic pain. Importantly, we have conducted several preclinical tests to confirm LX9211’s independence from the opioid pathway, and thus far we have found no concerns around addiction with LX9211. We conducted single and multiple ascending dose Phase 1 studies in healthy volunteers to study the safety, tolerability and pharmacokinetics of LX9211. The studies supported the preclinical profile. LX9211 was well tolerated with dose-proportional pharmacokinetics that are supportive of once daily dosing. There were no drug-related serious adverse events, and the most common adverse events were headache and dizziness. Overall, we see LX9211 representing an innovative potential approach to treat neuropathic pain without the addictive potential of many of the current therapies and treatments. We have two Phase 2 proof-of-concept studies ongoing. One of them is the diabetic peripheral neuropathy pain study and another one in post-herpetic neuralgia. They are both double-blind, placebo-controlled, parallel-group multicenter studies. The DPNP study is a three-arm study, while the PHN study is a two-arm study. They both share the same primary endpoint, which is the change from baseline to week six in the average daily pain score. The DPNP study, because diabetic peripheral neuropathic pain is a more heterogeneous condition, we felt is important to have a relatively large study. And so we are enrolling approximately 300 patients across at least 30 U.S. sites. PHN is a more homogeneous disease, and so we can do a smaller study. We anticipate enrolling approximately 75 patients in this study. Patient enrollment and dosing is ongoing in both studies. We expect results from both studies towards the end of this year. I would like now to turn our attention to sotagliflozin and the recent data from our two studies, SOLOIST and SCORED, in heart failure. The SOLOIST and SCORED Phase 3 outcome studies have been completed and involved approximately 1,200 and 10,500 patients respectively. Both studies were presented during a Late-Breaking Session of the American Heart Association in November 2020 and concurrently published in two separate articles in the New England Journal of Medicine. Before delving into the data from SOLOIST and SCORED, I want to describe the reasons why we believe our data is especially compelling and differentiated from selective SGLT2 inhibitors. There is a growing body of evidence that highlights the potential cardiovascular benefits of SGLT1 inhibition, including a number of recent publications that suggest potential cardiovascular benefits of SGLT1 and lower glycemic variability. It has been reported in the literature that lower glycemic variability is linked to less left ventricular dysfunction and less risk of myocardial infarction and stroke. Benefits of lower glycemic variability through SGLT1 inhibition are also supported by human genetic studies in which people with a loss of function mutation in the SGLT1 gene show a decrease in postprandial glucose level, which has been linked to decreased incidents of heart failure, obesity, and mortality. As a result, we feel there is solid scientific support that SGLT1 inhibition is providing much of the cardiovascular benefits that we observed with sotagliflozin, a dual SGLT1, SGLT2 inhibitor, in SOLOIST and SCORED studies. The clearest evidence that sotagliflozin provides SGLT1 inhibition is represented on this slide, looking at the impact of hemoglobin A1C in patients with moderate and severe chronic kidney disease. SGLT2 inhibitors work through the kidney and so their effectiveness diminishes as kidney function declines. SGLT1 inhibition works through the gut and therefore, is independent of kidney function. In this slide, you can see that patients with severe chronic kidney disease or eGFR less than 30-milligram per minute per 1.73 square meters experienced a very clear and significant reduction in A1C. There has never really been any evidence of A1C benefit from any SGLT2 inhibitor in this patient population. A highly significant reduction in A1C was also observed in patients with moderate chronic kidney disease or eGFR between 30 and 60. The SOLOIST study was conducted in patients who had recently been admitted to the hospital for worsening heart failure and who had Type 2 diabetes. They were treated with sotagliflozin or placebo, while in the hospital or within a couple of days of discharge from the hospital. A number of heart failure studies have been conducted with SGLT2 inhibitors. But those studies have primarily evaluated patients who are stable and have returned home from the hospital. The SOLOIST patient population represented the time of the highest unmet need for those patients suffering from heart failure in a hospital setting. This graph shows the primary endpoint of total events of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits. Data from the study showed a noticeably clear effect that separated early between sotagliflozin and placebo arms. The hazard ratio was 0.67, meaning there was a 33% reduction in the risk of cardiovascular death, rehospitalization for heart failure, or an urgent heart failure visit. What makes the results even more profound is the call out in the first month to the right of this slide. The effect separated very early, and we saw statistical significance by 28 days with a hazard ratio of 0.61. We believe that this early effect could provide an important benefit to the entire healthcare system by reducing near-term hospital readmissions of these patients. The SCORED study was conducted in patients with Type 2 diabetes, severe or moderate kidney disease, and cardiovascular risk factors. The design of this study was more akin to some of the other cardiovascular outcome studies that have been conducted with selective SGLT2 inhibitors. The primary endpoint for the SCORED study was the same as SOLOIST, a composite of cardiovascular death, hospitalization of heart failure, and urgent heart failure visits. In this case, our primary endpoint had a hazard ratio of 0.74 or a 26% risk reduction. Once again, another highly significant p-value and really compelling separation that started early and continued throughout the study. Now let's look at a post-hoc analysis of total fatal or non-fatal myocardial infarction and fatal or non-fatal stroke. We saw a favorable hazard ratio of 0.68 and 0.66, respectively. Similar results have not been observed with selective SGLT2 inhibitors. One of the most interesting findings from these two studies is shown on this slide. We took a look at the hazard ratio across the entire spectrum of left ventricular ejection fraction in heart failure patients in both SCORED and SOLOIST studies. There is a trend showing that as the ejection fraction increases, the hazard ratio actually decreases. This trend has not been seen in any study and makes clear that our dual SGLT2, SGLT1 inhibitor sotagliflozin provided benefit across both reduced and preserved ejection fraction patients in those studies. We are especially excited about the robust risk reduction of sotagliflozin in the entire spectrum of preserved left ventricular ejection fraction patients who currently have limited treatment options. That similar data also holds true for MACE events, which include cardiovascular death, non-fatal stroke, or non-fatal myocardial infarction, where we see the same trend as a function of ejection fraction. Based on very encouraging data from these two studies, which I just reviewed, the FDA agreed that the results of SOLOIST and SCORED can support a New Drug Application submission for an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with Type 2 diabetes with either worsening heart failure or additional risk factors for heart failure. We are very excited about the broad spectrum of cardiovascular benefit that our dual SGLT2, SGLT1 inhibitor, sotagliflozin, demonstrated in both SOLOIST and SCORED trials, including differentiation in rapid benefit in a hospital setting, the benefit in both reduced and preserved left ventricular ejection fraction and the substantial reductions in myocardial infarction and stroke. These are all unique outcomes compared to what has been seen to date with selective SGLT2 inhibitors. We are very pleased with the regulatory feedback we received from the FDA, and we plan to move expeditiously forward with our partnering discussions and with an NDA filing this year. With that, I'd like to turn the call back to Lonnel to discuss the potential market opportunity for sotagliflozin in heart failure.

Thank you, Praveen. Concurrently, with our partnership discussions, we actually had to take a step back a bit and do a little work to build our own understanding of the overall heart failure market and where sotagliflozin might strategically fit in that market, some of which I'll share with you now. Based on our market assessments, we feel that sotagliflozin may have a differentiated product profile with unique advantages in the treatment of heart failure. We believe that data from the SCORED and SOLOIST studies support a label for sotagliflozin to treat worsening heart failure or risk factors for heart failure in patients with Type 2 diabetes. We take a moment to note that ENTRESTO just received a label expansion from the FDA to include a more general range of chronic heart failure with a preference for patients with a left ventricle ejection fraction below normal. We believe this approval represents or presents a significant opportunity for sotagliflozin. Since data from the SCORED and the SOLOIST studies have shown heart failure benefits across the full range of the left ventricle ejection fraction spectrum, we feel that the data supports a broad label for the treatment of heart failure that does not distinguish references to HFrEF and HFpEF. The heart failure market has seen consistent growth that has the potential to accelerate tremendously in the next few years as new innovations enter the market to treat the sizable population with a high burden of disease, especially in the larger HFpEF population. There are nearly 1 million hospitalizations per year in the United States for heart failure, which is exactly where our SOLOIST study looked to see the impact of sotagliflozin in this patient population. This was a big risk for the design of this study. There has been a lot of literature around the conversions of heart failure and Type 2 diabetes, and one 2016 publication looking at 160,000 hospital admissions across the United States for heart failure found that approximately 44% of the patients presented with Type 2 diabetes. When you look at the overall heart failure population, the proportion of the HFpEF patients in the hospitalized setting has been increasing over time. There have been a number of new entrants into the HFrEF arena but only sotagliflozin has shown clear clinical benefit across the full range of the more difficult-to-treat HFpEF population. Overall, we believe that the clinical data for sotagliflozin supports an indication to treat across the full spectrum of left ventricle ejection fraction and would be an especially welcome new entrant for the larger HFpEF population. According to global data, the current market for chronic heart failure is approximately $4.2 billion in the United States and is expected to grow at 18% per year in the upcoming decade to reach $16.6 billion in 2028. As you can see, we feel that the overall market potential for sotagliflozin is substantial and is a primary reason we have prioritized accelerating to file the NDA in heart failure in the second half of the year. There is great value and an urgent need for a treatment like sotagliflozin, and we do not want to lose a day. Now with that, I'll turn this call over to Jeff to walk you through our financial results for the fourth quarter and then give some financial guidance for 2021.

Thank you, Lonnel. To begin, I will discuss key aspects of our fourth quarter financials. More financial details can be found in the press release that we issued earlier today and our upcoming 10-K SEC filing. As indicated in our press release, we had minimal revenues in the fourth quarter of 2020, primarily due to the elimination of product revenues as a result of our sale of XERMELO during the third quarter of 2020. Research and development expenses for the fourth quarter decreased to $1 million from $40.6 million for the corresponding period in 2019. This was primarily due to a reduction in external clinical development cost estimates related to sotagliflozin. This was a one-time adjustment and not indicative of our expected research and development expenses moving forward. Selling, general, and administrative expenses for the fourth quarter decreased to $6.4 million from $14.6 million for the same period in 2019, primarily due to reductions in personnel and elimination of marketing expenses following the sale of XERMELO. In total, we had a net loss for the fourth quarter of $5.5 million or $0.04 per share as compared to a net loss of $51.1 million or $0.48 per share in the corresponding period of 2019. Our net loss for the fourth quarter included non-cash stock-based compensation expense of $2.7 million and $3.5 million, respectively. We ended 2020 with $152.3 million in cash and short-term investments as compared to $271.7 million as of December 31, 2019. We eliminated 95% of our debt during the year, reducing our overall indebtedness from $245.3 million at mid-year to $11.6 million at the end of the year on December 31, 2020. Now I will turn to our financial guidance for 2021. We expect our 2021 operating expenses to be in the range of $85 million to $100 million, which is a sizable decrease from the $204.4 million in operating expenses we had in 2020. We expect non-cash expenses to be approximately $11 million of our total operating expenses. Research and development expenses are expected to be in the range of $60 million to $70 million. This estimate includes the expected spend for our ongoing two Phase 2 clinical studies of LX9211, the remaining closeout of our sotagliflozin studies and the expected cost to submit a New Drug Application for heart failure as well as investments in preclinical and discovery stage programs. We expect G&A expenses to be in the range of $25 million to $30 million. Overall, we expect that our current cash and investments will be sufficient to fund our operations through 2022 and into 2023. I will now turn the call back to Lonnel.

Jeff, thank you. I think let's open the line up for questions, and we'll go from there.

This is Carly on for Yigal. For LX9211, can you talk about the rationale for running a larger three-arm study in diabetic neuropathic pain, where you're testing two different doses versus running a smaller study in post-neuropathic neuralgia that has two doses? And then, I guess, the second part to the question, based on the mechanism of action, is there a reason to think that LX9211 should work better in one indication versus the other?

Thanks for the question. I'll turn that question over to Dr. Tyle.

Carly, I think let me separate your question into two parts. The first part is why the larger trial with DPNP compared to PHN? And what other indications potentially could work with 9211? Those are the two questions. So the first question is, when you look at the DPNP study, as I said in my remarks, diabetic peripheral neuropathic pain is a heterogeneous disease and different patients present themselves with different etiologies. So we've figured that we better study two different doses because different patient populations may need different doses, number one. And number two, because of the heterogeneous behavior of the disease, we wanted to make sure that we were not missing a positive signal by doing a very small study. Hence, the number of patients is set at 300. Now compared to PHN, which is more or less a very homogeneous disease, when we look at the preclinical data, we studied a 30-milligram per kilogram dose, which more or less translates to where we are with 200/20 dosing which we are studying in the clinical study. As for your second question, which is what other indications 9211 may work on? I think besides these two indications, we are also doing preclinical work in various other CNS diseases. What we have not mentioned today because we have not finalized it yet is what other disease areas we may be studying with this compound. We believe this compound is very versatile and could be very useful in other neuropathic pain indications and other CNS diseases.

Thanks, Praveen.

Great. That's really helpful. And then just switching over to sotagliflozin for heart failure. Can you broadly characterize the level of interest you're receiving from potential partners there? And maybe just talk a little bit about what you see as the characteristics of an ideal partner for the program?

Yes. I think the number one characteristic is that you have to find someone who believes as you believe. We took a step back, and I alluded to this at the JPMorgan Conference, we needed to step back a little bit to make sure that we can get the right kind of deal. It was important to do that because we hadn't done any market research. We got the data and interest started to show up. It's not a good idea to entertain that so dramatically before you have your own research done, before you have your own KOL engagement. So we took the time to do that. As we did that, our enthusiasm about what we had in hand grew quite remarkably. You can only imagine that then shifts the conversations that you have in partnership discussions. I would say, overall, we've had fairly robust conversations with a number of parties, and we continue to have discussions with a number of parties. I think now that we have the data in hand of our own market research, our own KOL findings, it puts us in a better position to do two things. One is to know for ourselves what value looks like; and two, how to influence others to see the world as we see it. That takes time sometimes. I think the challenge is that you have some players who will come in and just say there's another SGLT2, and the results are not similar. We have to help people through that and help them through not only with the science that we show them but also help them understand when we go out to market and test it. The conversations remain robust, and we intend to do something with someone who believes as we believe that this is a remarkable opportunity and it needs to be approached as such and not approached as a me-too. And that takes a little bit more time. But nonetheless, I think that's the way I would characterize the discussions.

So I guess, in showing the combined effect in the patient population between SOLOIST and SCORED, is it safe to assume that an NDA that you'll be filing will include data from patients with preserved ejection fraction from both trials?

Yes. The results we saw were consistent in both studies. It's just when you look at the spectrum of patients who had a history of heart failure, which is everybody in SOLOIST and the patients at SCORED, it's a very clear and really kind of unique perspective across that entire ejection fraction, but the results were consistent in both of the studies.

Yes, Stephen. I think the agency is going to want to see all of that data. I think we're pretty confident at this point. When we look at the confidence that comes from our position, to some degree, it's because ENTRESTO had its AdCom, and we looked at the questions that came from that AdCom. We looked at where the FDA was relative to HFpEF, how to define it. We saw a lot of variability in how people perceive HFpEF or what they call HFmEF that something that sits between reduced and preserved. What I found about that conversation is that they were trying to figure out if you going to label it, where was the real value. The reason I mentioned this is a great opportunity for sotagliflozin— we don't need to have that conversation because whether you look at rEF, HFmEF, or pEF, the overall rate of reduction was quite substantial and statistically significant. Even looking at the confidence intervals, you continue to see significance. So you just have a very robust response across the entire spectrum. That's very different from anything shared at the AdComs at the end of the year that the FDA was considering. The fact that they found ways to label ENTRESTO gives me great confidence that there should be a way to label us across the entire spectrum.

Understood. I think you had previously suggested that a regulatory filing, an NDA, would unlikely occur in the absence of having a partnership in hand. So is the partnership still a rate-limiting step to the regulatory filing? Or is that something that you guys feel you can proceed with on your own while some of these partnering discussions continue to crystallize in the background?

Steve, I reserve the right to change my mind. Let me just say I changed my mind. Part of that is because we went out and did the work. We spoke to key opinion leaders. We did the market research. The deeper we went, the more amazed we were with our data. Therefore, we learned very quickly that we shouldn't waste any time waiting for a partnership to materialize before we make the decision to go forward because we now have the advantage. Others are going to have to demonstrate what we show. The best way to set that stage is to get it in front of the regulatory agency. So we made the decision not to wait for a partnership to materialize to create value; one of the best ways to create substantial value is to move toward the NDA filing. We have prioritized it because my confidence in what we have in hand is growing.

This is Yuko on for Jess. Just real quick, what are you seeing as a potential read-through from upcoming data for Jardiance and Farxiga with them both expected to read out data for ejection fraction in terms of how that would possibly impact business development for sota?

It goes back to the answer I just gave: that's why you don't waste a day on getting your NDA and setting the path for everybody else to follow. I think these are two smart companies and they know how to develop. There may be some degree of success that they're going to have. But I think it's going to be very interesting to get anybody to match the data of sotagliflozin. The reason we believe that is that fundamentally, we look at why we see the results we've seen. We believe that the SGLT1 is contributing positively to the outcome that we see. Therefore, given our unique mechanism, we ultimately think we will have uniqueness. Now that has to be seen when they announce their data. We must watch for is that the cutoffs should not only look at selective areas. Look at the entire spectrum since HFpEF is about 50% of the market. If you focus solely on cutoffs below 60 or somewhere around 50 and so forth, you're cutting off a considerable market portion because you can't show benefits. What we've been able to show, regardless of whether the cutoff is 40, 50, 60, or 70, you see a hazard ratio, and you observe statistical significance. So that is what should be examined from these other trials. If you do not see that, then the advantage remains with Lexicon. Now that you're indicating moving right away on filing the NDA on your own, is there any potential for that to impact the commercialization strategy? Or is it a partner still going to be gating to that? The commercial part, that's where we need a partner; there's no question about it—a well-positioned partner or a partner who has the resources to be well positioned. We've had folks approach us who are interested but, quite frankly, have seen a meaningful opportunity that may not be ideally positioned in heart failure today but want to be. The key is that you need to find someone who fundamentally sees the world the same way. We've come out of a significant alliance where we diverged in our opinions. We feel confident that our opinion was right coming out of that alliance. The data now bears that out to be true, but we lost a lot of time. We can't afford to do that again. We need to find someone who aligns with us and is willing to invest to compete, to launch the product in the heart failure market. There are very few drugs available right now. This is why I remind folks when we talk to them. How many drugs can you name today with an indication for HFpEF? There aren't any. The closest is ENTRESTO, which has moved toward the HFpEF arena by broadening their label. But the benefit was observed below 57 in the normal population. A massive need exists for more compounds in HFpEF, and that is the fastest-growing and significant part of the market right now. We have evidence to support that and we'll have to wait and see if anyone can match that. For now, we have shown it, and we need a partner that can come in and help us tell that story.

In the past few weeks, there have been a few cases we've seen where it seems like the FDA and some companies with drugs under review, you haven't really been on the same page. Regarding sotagliflozin, can you speak to any dialogue you've had with the FDA since the update you gave in January? I know you mentioned the ENTRESTO label, but anything else that gives you confidence around your conversations with the agency and the filing pathway for heart failure?

That's a great question. I would say we haven't had much more dialogue with the agency since the last update we provided. What we have done is watch very carefully the advisory committees they have had, and we gathered information from both. I think it was clear that the agency was looking for something that they could approve that offered benefits for patients in this market given the limited ongoing treatment options. I also believe the panel was striving to dive deeply into the data presented to them to find hope for a therapeutic option for patients in the HFpEF arena. We've gained confidence from insights from those two advisory committees in terms of what the FDA seeks and, quite frankly, it's very consistent with our previous dialogues and what we plan to do regarding our filings. Therefore, our confidence comes primarily from that. Regarding LX9211, I know we are maintaining the timeline of data from both studies by year-end. But in terms of enrollment, have you seen any change in the pacing of enrollment or getting sites up and running? Now that COVID is declining to some degree and we have vaccines ramping up. Has anything changed there that gives you greater confidence in those time lines? Well, we had to plug in risk mitigating strategies because we started to see enrollment impacted by the last wave of COVID. If you look at some states and their efforts to close down and try to mitigate the situation, it had an impact. We did notice that and prepared risk mitigation strategies to keep us on time without compromising the study. Therefore, it did have an impact but I believe the risk-mitigation plan that we implemented should allow us to remain on track for the end of the year. We are hopeful. As people’s confidence grows about the vaccine and as states start to ease restrictions a bit, I think people will feel more comfortable coming out of their homes especially those with chronic conditions such as diabetic peripheral neuropathic pain. When that happens, I believe our mitigating strategy will allow us to accelerate even faster. For now, I would say that we saw risk to the study in terms of enrollment but we placed that plan in place and are hopeful that the environment will allow us to stay on track.

I just want to follow up on 9211, looking ahead to the data readout towards the end of this year. What are the expectations around ADPS change and placebo response rates between the DPNP and also the PHN trials, and in terms of any type of rescue pain medication, is that included in the trial or not? Some additional color there would be helpful.

Yes, I appreciate the question, but I'm not answering any of them. A lot of the way we design and run this trial is to maintain as much of a proprietary advantage as we can so that we get to keep some advantage in how we're conducting them. These are all very good questions, but we haven't disclosed details regarding that. As we make more progress in future updates, we may adjust that stance. But for now, we're not getting very deep into those kind of details.

There are no further questions at this time. I'll now turn the call back over to the presenters for closing remarks.

Well, thank you. I appreciate all of those who joined us today. I just want to say that 2021 is off to a terrific start for Lexicon. I think we ended the year very strong. We recapitalized the company, dealt with our balance sheet, and restructured our company to be very much focused on the assets at hand. I think the sotagliflozin data, as Steve asked about, do we file it with a partner or without a partner? Because we were able to capitalize the company, we're in a position to file regardless of when a partnership comes along because the value will only continue to increase. Therefore, we've made the decision to prioritize following sotagliflozin. My confidence in this compound is only growing every day, and we need to make it a priority. That being said, we have not taken our foot off the gas with LX9211. I believe this is the transformative brand that will be the future of Lexicon. We did see some issues that needed to be mitigated in terms of enrollment, given the environment we operate in, but we believe we have plans in place to keep the program on track without compromising outcomes. Lastly, as we approach the end of this year, we hope to share details on some of the other extraordinary work we're doing on our discovery programs. We are returning to our R&D roots and moving things forwards that we will start talking about as we near the end of this year. With that said, I hope you all have a good evening. Thank you.

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