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Welcome to the Lexicon Pharmaceuticals Fourth Quarter 2024 Financial Results Conference Call. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a brief question and answer session. As a reminder, this call is being recorded today, March 6, 2025. I will now turn the call over to Lisa DeFrancesco, SVP, Investor Relations and Corporate Communications for Lexicon Pharmaceuticals. Please go ahead, Lisa.

Thank you, Gigi. Good afternoon, and welcome to the Lexicon Pharmaceuticals Fourth Quarter and Full Year 2024 Financial Results Conference Call. Joining me today for prepared remarks are Dr. Mike Exton, Lexicon Pharmaceuticals' Chief Executive Officer and Director, and Scott Chianti, Senior Vice President and Chief Financial Officer. Craig Granowitz, Senior Vice President and Chief Medical Officer, will also join us for Q&A. This afternoon, Lexicon Pharmaceuticals issued a press release announcing our financial results for the fourth quarter of 2024, which are available on our website lexpharma.com and through our SEC filings. A webcast of this call, along with the slide presentation, is also available on our website. During this call, we will review the information provided in the release, provide a corporate update, 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 related to the safety, efficacy, clinical development, regulatory status, and therapeutic and commercial potential of pilabapadin LX9851, sotagliflozin, and our other drug programs, as well as our business generally. These statements may also include characterizations and projections relating to the clinical development, regulatory status, and market opportunity for our drug programs, the commercial performance of MpEF for heart failure. This call may also contain forward-looking statements related 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, and we refer you to our most recent annual report on Form 10-K and other SEC filings for detailed information describing such risks. I would now like to turn the call over to Mike Exton. Mike?

Hey. Great. Thanks, Lisa, and good afternoon, everyone. Thanks for joining the call. Look, we have had a busy start to 2025 already, including our announcement on Monday of top-line results from our PROGRESS Phase 2b study of pelabapitan in diabetic peripheral neuropathic pain or DPNP. But as we take a moment to look back and reflect on 2024, I am immensely proud of the resilience and adaptability of the team in keeping our pipeline of novel moving forward and advancing our lead to succeed strategy. Last year, we strategically repositioned Lexicon Pharmaceuticals to focus the company and its resources on our clinical development programs. Some key highlights from these programs included the early completion of enrollment for our PROGRESS study, great progress in our pivotal Phase 3 Sonata HCM study of sotagliflozin in hypertrophic cardiomyopathy (HCM), where we continue to enroll patients as planned, advancing IND enabling studies of LX9851 in obesity and related cardiovascular disorders. Lastly, we reinvigorated our business development efforts, including a significant licensing agreement with Beatrice for sotagliflozin outside of the US and Europe. I want to begin today's overview with our most recent significant development. On Monday, we issued a press release and held a conference call to discuss top-line results for PROGRESS, the Phase 2b dose-finding study of pillabapentin, our oral non-opioid drug candidate for DPNP. Now, the two most important takeaways from our top-line announcement this week are, first, in all doses in the PROGRESS study, including placebo, we observed a clear separation in ADPS from baseline, with the 10-milligram dose also showing meaningful improvement compared to placebo.

Secondly,

all pillabapentin-treated arms showed improved tolerability when compared with our previous release DPN study. Indeed, the 10-milligram dose of pillabapentin showed particularly better tolerability as compared to relief. For these reasons, we successfully achieved our corporate objectives for PROGRESS with the 10-milligram dose. These data, in combination with the data from the release study, give us greater confidence in the potential of pillabapentin to be the first novel oral, non-opioid DPN medication in more than two decades. We are moving forward with a 10-milligram dose. As you can see in this slide, filobapadine 10 milligrams performed strongly, improving ADPS at week eight, reducing it by 1.74 points from baseline. As we continue to analyze the data, there are already signals that give us even greater confidence to advance the 10-milligram dose in the pivotal trials. Pooling the two arms that utilize 10 milligrams, the 10-milligram dose plus the 10 plus plus the 20 plus 10 arm, this post hoc analysis shows an approximately 0.6 ADPS reduction versus placebo as early as week two, which is maintained throughout the treatment period. Interestingly, while the pain reduction curve of the placebo arm appears to flatten out in the last four weeks of the trial, the 10-milligram dose continues to consistently reduce ADPS scores, suggesting that in pivotal trials of 12 weeks duration, further separation may be achievable. Furthermore, as we outlined on Monday, the 10-milligram dose was well tolerated in PROGRESS, as many patients with 10-milligram pillabapadine as with placebo completed the trial, conclusively ascribing the tolerability performance in the previous release study to the day one tenfold loading dose. This gives us confidence in the tolerability of 10 milligrams of pillabapadine in Phase 3 trials. We continue to analyze further data and look forward to presenting the full findings from the PROGRESS study at a future medical meeting. Now, I want to talk about what pillabapadine can potentially mean for patients. DPNP is a large and growing condition that impacts approximately nine million people in the US. It is a chronic and progressive pain disorder that severely impairs people's quality of life, with the majority of patients experiencing moderate to severe pain. When we speak with patients and physicians, it is truly devastating their ability to sleep at night, their mental health, and their relationships. DPNP can also lead to loss of sensation, loss of balance, falls and fractures, and a wealth of other complications. Importantly, currently available treatments simply do not provide adequate relief. It is estimated about 60% of patients have tried multiple therapies, and only a third are somewhat satisfied with their treatment. In market research, we heard numerous HCPs and patients report an immense need for new treatment options, and in particular, a simple, easy-to-use non-opioid treatment option for DPNP. Finally, with about a third of DPNP patients still resorting to short-term opioid use for pain relief, even today, when we know the potentially devastating effects of these treatments, this space is primed for reform. HCPs, legislators, and policymakers, via initiatives such as the Alternative to Pain Act, provide tailwinds to support movement towards new non-opioid options. Next, I would like to discuss LX9851, where we are continuing to advance IND enabling studies. LX9851 is our first-in-class oral ACSL5 inhibitor for the treatment of obesity and related cardiometabolic disorders. In November, we presented clinical in vivo data from two studies related to LX9851 at a BC week. The first study showed that treatment with LX9851 resulted in significant reductions in weight, food intake, and fat mass in diet-induced obese mice, and that LX9851 mitigated weight regain following discontinuation of the GLP-1 analog semaglutide. The second study characterized the novel mechanism of action of LX9851 and how it activates the ileal brake to induce satiety and lower desire for additional food consumption. We remain on track for an IND submission for LX9851 in 2025 as we evaluate potential partnership opportunities for this innovative mechanism. Now, I want to briefly touch on the current status of sotagliflozin. We have a significant potential opportunity to expand our label in hypertrophic cardiomyopathy, a disease state with high unmet need that impacts about one million patients in the U.S. We are currently enrolling Sonata HCM, a global pivotal Phase 3 study including patients with both obstructive and non-obstructive HCM. Upon completion of the HCM study, with additional evidence and data in hand, we will revisit the totality of the sotagliflozin asset potential in the US. In terms of what we are doing today, though, as we bridge to this future opportunity, as you can recall, we made the necessary decision to cease all promotion of Impepper in the U.S. heart failure due to the difficult market access environment dominated by two major SGLT2 inhibitors. Currently, sotagliflozin is available on the US market with our continued commitment to maintain awareness and provide tools to support patients in an extremely cost-effective approach. Outside of the US and Europe, we are actively working with our exclusive licensee, Beatrice, on supporting their efforts towards registration and regional development. Our Medical Affairs Data Generation and Public Patient Act activities remain ongoing, and we continue to engage with the scientific community through numerous investigator-initiated third-party funded studies to build upon our compelling body of medical evidence in CB conditions and now comes and support sotagliflozin as a differentiated inhibitor of both SGLT1 and 2. To that end, I wanted to briefly acknowledge a notable recent publication in the Lancet Diabetes and Endocrinology, which highlighted the effects of sotagliflozin to reduce major adverse cardiovascular events or MACE, myocardial infarction, and stroke among patients with type 2 diabetes, chronic kidney disease, and high cardiovascular risk. The finding shows that sotagliflozin significantly and meaningfully reduces MACE versus placebo, demonstrating early and broad cardiovascular protection in this population. This research also highlighted that sotagliflozin is the only SGLT inhibitor to show significant reductions in both MI and stroke, indicating the potential role of SGLT1 inhibition in reducing ischemic events, an important distinction from selective SGLT2 inhibitors. As I shared just a moment ago, this supports our goal of demonstrating differentiation of sotagliflozin and presents compelling additional is but Beatrice on regulatory submissions in key ex-US and ex-European markets throughout 2025. I will now turn it over to Scott to walk you through our financial results for the quarter and the year ended December 31, 2024.

Thanks, Mike. Lexicon Pharmaceuticals ended 2024 with $238 million in cash, cash equivalents, and short-term investments, as compared to $170 million as of December 31, 2023. As noted in this afternoon's press release, we reported $26.6 million in revenue in the fourth quarter and $31.1 million in revenue for the full year 2024. Revenues for MPIFA were $1.7 million in the fourth quarter of 2024 and $6 million for the full year 2024. Total revenues for both the fourth quarter and full year include an upfront payment of $25 million received in connection with the Beatrice licensing agreement. Research and development expenses for the fourth quarter increased to $26.7 million from $14.8 million in the fourth quarter of 2023. Full year 2024 research and development expenses increased to $84.5 million from $106 million in 2023, primarily due to our investments in Phase II and Phase III clinical trials, including the Sonata Phase III study of sotagliflozin in HCM and the PROGRESS Phase 2b study of pilavapodin in DPNP. Selling, general, and administrative expenses for the fourth quarter of 2024 were $32.3 million, comparable to the $32.6 million of SG&A expenses in the fourth quarter of 2023. Full year 2024 SG&A expenses increased to $143.1 million from $114 million in 2023. This increase in 2024 reflects higher marketing costs related to the commercialization of IMVEVA and increased employee salaries and benefit costs, prior to the reduction in our field sales force in late 2024, as well as severance costs associated with our strategic repositioning. Net loss for the fourth quarter of 2024 was $33.8 million, or $0.09 per share, as compared to a net loss of $49.8 million, or $0.20 per share, in the corresponding period in 2023. Net loss for the full year 2024 was $200.4 million, or $0.32 per share, in 2024, as compared to a net loss of $177.1 million, or $0.80 per share, for the same period in 2023. During 2024, Lexicon Pharmaceuticals took steps to first reduce and then to eliminate all promotional efforts for Empeza. These included a significant reduction of employees and elimination of all promotional efforts for Empathy and heart failure in the US. We believe these steps will reduce operating expenses moving forward. For 2025, we expect total operating expenses to be in the range of $135 million to $145 million. We expect research and development expenses to be in the range of $100 million to $105 million, and SG&A expenses to be in the range of $35 million to $40 million. Research and development expenses include costs associated with ongoing development of sertagliflozin for HCM, preparations for the Phase III development of pillvaparinin, and preclinical costs associated with preparations for the IND filing of LX9851. Research and development expenses for 2025 do not include the cost of pivotal Phase III trials for pilivapodin, as the size and scope of these trials will be determined as part of our end of Phase II review discussions with the FDA. I'll now turn it back to Mike for closing remarks.

Thanks, Scott. In summary, we have a full and exciting year ahead. The work we did in 2024 really set the foundation, and we look forward to updating you all as the year progresses. For Pillavapadine, we have a number of important upcoming catalysts, including disclosure of the full PROGRESS dataset, the end of phase two meeting with the FDA, and data presentations at upcoming endocrinology and pain-focused medical meetings. In addition to the important upcoming milestones we discussed today, we are also very actively engaged in partnership discussions that will enhance our clinical and commercial capabilities and help us maximize the potential of all of our novel therapies. This will be a critical focus for the company in the coming months. So with that, Scott, Craig, and I have time to take all of your questions. So I'll turn it back to you, operator.

To withdraw your question, please press star. Please standby while we compile the Q&A roster. Our first question comes from the line of Joseph Stringer from Needham and Co.

Hi. Thanks for taking our questions. I want to ask about the 9851 oral obesity asset and the clinical development plan there. A couple of questions on that. Is that only being considered as a combo therapy with, say, a GLP drug, or is there an option for monotherapy? And then what are the potential indications and trial designs that you are thinking of for an initial phase one? Lastly, if a decision is made to ultimately partner that program, how much clinical data do you think you would need to generate before it would make sense to engage or turn over to a partner?

So Joey, I'll answer the first two questions and probably turn it back over to Mike for the third. We really see this molecule as being developed both as monotherapy and combination therapy. Monotherapy alone or monotherapy after discontinuation of an injectable or other GLP-1 agonist, knowing with the data that's come in with the injectables, at least a vast majority of patients do not remain on therapy for more than a year. In fact, the median duration is somewhere between six and twelve months. What we have demonstrated in the animal models is the activity of the drug is independent and additive on top of semaglutide, even maximum dose semaglutide. If you withdraw the semaglutide and then add the 9851, you largely maintain the weight loss, whereas if you do not add the 9851, weight returns very quickly to baseline, which is also a situation in patients. We see that there is an opportunity in both mono and combination therapy. The second question on the clinical program, I think the phase one program is going to be pretty standard. What we have communicated before is we have a few critical goals that would be a part of the phase one program. First and most importantly is do patients actually lose weight similar to what we see in the animal models? The second is the tolerability of the therapy because, again, you always have to wonder in these treatments. The question is will it be well tolerated, especially with the novel mechanism of action like the ileal brake? We have not seen anything in the animal models to suggest that would be an issue with tolerability, but that would be an important component. The third is to demonstrate that there is a clear mechanistic differentiation from the GLP-1 mechanism. So I think those would really be the three critical goals that we have certainly thought about running the phase one program. I'll turn it back over to Mike for the last part of your question.

Thanks for the question. As you could imagine, with a completely novel and orthogonal mechanism to the GLP-1 and incretin-based mechanisms, there are a number of companies that have not only been interested in this particular asset but have engaged in the data over the last months. We have been talking to a number of players. What it would take to move into a partnership from a data perspective is really quite varied. We are prepared if we do have the right partner with the right conditions at any particular time to move into partnership because ultimately, we believe that this program is best served with a partner to really capitalize on the breadth of indication, again, with the potential for indications beyond obesity as well as the commercialization of this particular mechanism ultimately. So that's where we are at with 9851 and potential partnering opportunities.

Great. Thank you so much for taking our questions.

Thank you. Okay. One moment for our next question. Our next question comes from the line of Yasmeen Rahimi.

Hi. This is Hina on for Yas. Thank you for taking our questions. My first question is, could you kindly provide some color on how enrollment is progressing into your study and when you expect enrollment completion? With that, how soon could you engage with the FDA for the end of phase two meeting for Philip Apitin and start planning for phase three? Finally, what are some of the rate-limiting steps to complete for the IND filing for 9851, which was previously discussed? Thank you.

Alright. Three great questions on three different programs. I'll try to have a stab at those. Thanks, Hina. I'll answer them in order. On the HCM program, we have been really pleased by the feedback we have gotten. We have had a number of investigator meetings both in the US and outside the US. We focused first and initially on opening sites in the US. We have communicated that we are targeting about thirty sites in the United States, a hundred and twenty sites overall, with a target enrollment of about five hundred patients, two hundred and fifty each stratified for obstructive and non-obstructive. I can say that we have made outstanding progress in getting all the government approvals necessary to have those conversations in countries outside the US, and we have sites open in non-US countries right now. Again, we have not been forthcoming with exactly what those are, but we can say that we are opening sites on plan. We have patients that are actively in screening and actively in treatment today, similar to the timelines we have set. The timelines, I think we have talked about, is that we are looking to have final study results towards the end of 2026, which means that we would be filing with the FDA probably sometime in the first quarter of 2027. Those are our current timelines. Obviously, it's early days in the trial, but those are the timelines that we have put forward, and there's nothing at this point that we think is going to be significantly changing those timelines at the moment. If that answers your questions on HCM, I'll move forward to filivapoden. For Pillavapodin, as Mike mentioned and I think we mentioned in the call on Monday, we are really looking to get down to the FDA and have the end of phase two meeting sometime in the second half of this year, with the possibility of starting the phase three program before the end of 2025. Obviously, that will be dependent on a number of other factors, but those are the timelines that we feel comfortable with. Just to reiterate what Mike said, we are more confident than ever in that ten-milligram dose being the right dose, and the PROGRESS study really clarified the open issues that we had going into the study about what is the best dose to go into phase three, balancing both safety and efficacy, and do you need the loading dose or not? We feel quite strongly positive now to move to the end of phase two, publish the data this year, and then move into phase three. On 9851, we mentioned, I think Mike talked about, that our plan is to have all of the IND enabling studies done this year to get down to the FDA and have a meeting and be ready to start the first in human studies before the end of the year. That's the timelines that we continue to track to. We are doing all of the IND enabling studies right now. We had to do the dose finding from the animal studies to do the final toxicology studies that are required as part of the standard IND package. We are working actively against those targets.

Thank you so much.

Thank you. One moment for our next question. Our next question comes from the line of Joe Pantginis from H.C. Wainwright.

Everybody, good afternoon. Thanks for taking the questions. Two questions, if you do not mind. For pillvapatin data that you just put out, sort of a looking forward question. Craig on the call earlier said some broad strokes as to what the phase three program might look like. Can you discuss anything right now with regard to what you feel might be the key open questions and or wish list that you might have going into the FDA meeting, and, of course, they could absolutely change tomorrow.

Yeah. Joe, great question. I think we mentioned perhaps at least in passing on Monday some of the critical things that we are going to look at as we get the final dataset in. A couple of them we talked about. Some of the key secondary endpoints that we think are most meaningful to patients, as Mike talked about, is particularly sleep interruption and burning pain. Those are going to be important endpoints that we want to take a look at as we get the full data set in. Another one that we believe is pretty important to look at is the use of the acetaminophen rescue protocol. As you remember from relief, that correlated really nicely with response. There was much greater and earlier use of the acetaminophen rescue in the placebo arm than in the active arm. We feel comfortable that those three particularly are going to be important elements that will be consistent or hopefully consistent with the primary endpoint data that we shared and were certainly consistent in the relief study. I think the other area that we have an interest and I know a number of people that have asked have interest is what was the response regardless of the underlying single DPNP medication use. As a reminder, in relief, we demonstrated activity independent from the underlying DPNP medication and on top of the DPNP medication. I think that is going to be another important question because I think going into phase three, if we could demonstrate we have activity both with or without underlying DPMC medication here. I think that will be very important for patients, healthcare providers, and payers to know. We will also continue to look at some of the additional safety parameters in reference to DPMP use, looking at that in some of the demographic factors. As I think we mentioned, there were some notable differences in the demographics, particularly the representation of black Americans in the trial was nearly double. We will continue to look at some of those factors as well. Hope that was not too long a list, Joe.

No. No. That's fantastic. I appreciate that color. Just quickly, I guess, a financial logistical question, if you will. Just wanted to make sure have the MPEPHA one-time charges worked through the system already, or should we expect any for the first quarter?

Hey, Joe. It's Scott. No. I would say that it's a safe assumption that all the costs were certainly accrued as of the end of the year.

Perfect. Thanks for all the color, guys.

Thanks, Joe.

Thank you. One moment for our next question. Our next question comes from the line of Andrew Tsai from Jefferies.

Hey. Thanks. Good afternoon. I appreciate all the updates. Maybe two questions on pain on my side. For the upcoming FDA end of phase two meeting, could it make sense to ask them if this phase 2b counts as a supporting pivotal? By extension, do you have a base case or upside case internally? Secondly, at this juncture, do you think you would be powering the phase threes to what you saw in the phase 2a or the phase 2b for the ten mg dose?

Yeah. Andrew, thanks for the question. Certainly, that would be an upside in our current scenario planning of having this trial be counted as a pivotal. We would see it counting strongly as a supportive trial, but our base assumption would not be that this was a pivotal trial. I think as we previously shared, our current thinking, which obviously will be impacted by FDA, is that we would be looking at two pivotal trials going into the phase three program, each one of which would have roughly three to four hundred patients in size. To your question, we would probably power it similarly to how we powered both of these current trials for the statistics of a 0.6 on a placebo-adjusted basis. I wanted to reaffirm one of the points that Mike made in passing. We demonstrated in the PROGRESS study that at the ten-milligram dose, the pain scores continue to decline at a linear rate that was really consistent from week three on. You saw a sharp drop in the first couple of weeks, and then the slope of the curve changed but remained pretty consistent from week three or so to week eight. We do not see any reason why that would particularly mitigate between week eight and week twelve. If you sort of straight line that out, we think that that pain score is going to continue to significantly drop. If you look at the placebo and what has traditionally been seen in pain studies of placebo, is that that tends to plateau at somewhere between four and eight weeks. You can already see hints of that in this trial and in the relief trials at the plateau that the placebo is beginning to plateau. We feel quite confident or comfortable that that wedge, that growing wedge of difference from the placebo in pain score to the drug, will continue to grow between week eight and week twelve. That 0.6 drop is something that we think we can comfortably achieve.

Thanks. Appreciate it.

Thank you. One moment for our next question. Our next question comes from the line of Roanna Ruiz from Leerink Partners.

Hi, all. This is Maizion from Milana. We just had two commercialization questions kind of around satagliflozin and HCM. For one, what are your thoughts around partnership and commercialization for that asset? It's kind of a two-parter. The second part being, how does that differ across different regions where CMI use may be impacted in countries of Africa and Asia? I think that we have seen that use is a lot less. I just kind of wanted your insights around that. Please, thanks.

No. Great question. Firstly, for HCM, ex-US and ex-Europe, that is entirely licensed to Beatrice, our Sodokoplasm partner. So in, if you like, the rest of the world, Beatrice and we're closely connected with them to help them in the registration process, etcetera, for HCM as well as the other indications. For the US and, well, for Europe, I think we've mentioned before, we do not have any intention in expanding our presence and certainly not our commercial presence outside of the US. We would be seeking a partner for Europe where there is pretty substantial CMI use, as you know. Then it comes to the US. Really, we feel we've got the expertise and capabilities to commercialize sotagliflozin for HCM. As we've mentioned before, it's going to be a very different payer situation for HCM as the first and only SGLT inhibitor approved for HCM to what we see for INPEFER in heart failure. That will provide us with a much different potential commercialization trajectory. One interesting and final aspect to that commercialization approach is unlike the CMIs, and I think this will continue both with currently approved and future approved CMIs, it will be used now in a pretty focused way in centers of excellence that treat HCM patients. General cardiology CHCM patients and are able to diagnose and the SDLT as a class is very well known by general cardiologists. Really, there's an opportunity. Although we certainly see ourselves playing a significant role commercially in the US, there may be other partnering opportunities as we move forward, but we will hold a very significant, if not sole, approach to commercializing that in the US.

Oh, great. Okay. Thanks for the added color. Actually, to follow-up on that then, as we think about the baseline characteristics for Sonata, are there any targets for the amount of patients that could be on background beta blocker or CMI therapy?

Great question, Mason. We have not put limitations on any baseline or background therapy. We took a very similar approach to what we did with the score and SOLOIST trials, where we included all patients with heart failure in those trials regardless of whether they were HEF ref or HEF def. In this trial, we're taking all patients that remain symptomatic as defined by a baseline KCCQ score. They can be on any underlying medication, including a CMI, in that regard. What we really care most about is that they have an adequate low KCCQ score at baseline. That's really the major criteria. As a reminder, also, the ejection fraction that we allow is an EF down to fifty percent. I think the opportunity to include both obstructive, non-obstructive background therapies that exist, including CMIs, and then EF down to fifty percent, as well as having the primary endpoint as KCCQ, the secondary endpoint is New York Heart. No requirement for all of the echoes that the CMIs require that has all of the other physiologic testing, the peak VO2 and others, that really make it very difficult to enroll those trials and limit the number of centers in those trials. We believe that our trial offers a number of different upsides in that regard.

Very helpful. Thank you all for the added color.

Yeah. Thanks, Mason.

Thank you. At this time, I would now like to turn the conference back over to Mike for closing remarks.

Well, thanks, everyone, for joining us this afternoon. It was great to have you all here and give you a complete update across the three pretty significant programs that we have for sotagliflozin, for filobabapentin, and LX9851. We've got a busy quarter ahead of us and really look forward to updating you as we progress throughout the quarter and indeed throughout the year. Thank you very much, operator, and see everyone later.