Thank you, everyone, for tuning in. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have the Lexicon team with me today. Sitting to the direct right of me is Craig Granowitz, CMO, and to his right is Mike Exton, CEO. Welcome, both of you.
Maybe to start, give us a brief overview of Lexicon, what you're trying to achieve, what you're working on, catalyst flow over the next 6 to 12 months. Could be helpful.
Yeah, no, fantastic. So delighted to be here. It's been a wonderful meeting so far, and in fact, an incredible 2025, really, for Lexicon up until this point. We've had a number of very significant advances of the pipeline over the last 11 months. Let me just outline briefly where we're at across those developments. First of all, for pilavapadin, our novel AAK1 inhibitor for neuropathic pain, we read out our phase 2b trial, the PROGRESS trial this year. Over the last six months, we've analyzed the totality of evidence from that phase 2 program and have submitted an end-of-phase 2 meeting request to the FDA and submitted our briefing book. That meeting will take place this year.
We are looking forward to engaging with them to understand their expectations around the phase 3 program, and being in a position to advance that into pivotal trials next year. At the same time, we are engaging with potential partners on looking at how we partner that asset and move that not only into pivotal trials but forward into a commercial product. That has gone incredibly well. Secondarily, for sotagliflozin, we are now accelerating the enrollment in the SONATA trial. This is a trial for non-obstructive and obstructive HCM, hypertrophic cardiomyopathy. It is enrolling incredibly well. We have now got all sites worldwide open. With that, the patient recruitment is really steadily increasing, and we expect to close the enrollment of that certainly in the first half of 2026, if not by the first quarter, if we continue to really perform very well there.
This is an incredible area where if we have data at the end of 2026, we could potentially be the first medicine that has positive data in non-obstructive HCM. As you know, there are current medicines that have had positive data in obstructive HCM, which is an important component, but a huge unmet need in non-obstructive HCM. That is a great opportunity for us. We have recently, with sotagliflozin, the same asset, re-engaged with the FDA around type 1 diabetes, as you are well aware, Andrew. We have had incredibly constructive engagement with the FDA ever since our end-of-review meeting in May of this year. We now have submitted to them a third-party investigator-initiated study, the protocol, the design, and in fact, some data from this open-label study that will support a potential resubmission for Zynquista.
It's really what the FDA has requested from us now for the last couple of years as new prospective data. In a somewhat unique position, the FDA has accepted this data or accepted this trial, which is an IIS from Denmark, as potentially being supportive of a resubmission. That's fantastic for folks with type 1 diabetes who've really been an incredible advocate for having this medicine approved. Finally, we earlier this year had a worldwide license, exclusive license with Novo Nordisk for our novel obesity agent, LX9851, that targets another novel target discovered by the Genome5000 platform. It was on us to complete the IND enabling studies for that asset. They're all now done. We've handed over the full data package to Novo Nordisk, who really have demonstrated their enthusiasm and desire to push this program forward at pace.
We're now waiting on them to prepare and submit the IND, and that will enable some early milestone payments of up to $30 million. We look forward to seeing how that asset progresses in the clinic. Really a heap going on for us, a number of catalysts across the cardiometabolic space, the neuropathic pain space, and obviously with obesity as well.
Great. Thanks. Three late-stage programs plus a very differentiated obesity program on top of that.
Right.
Okay. Maybe we can talk about type 1 diabetes. You alluded to how the FDA seems to be collaborative, but can you give us a brief history of what's happened since the initial CRL that you received? What exactly was the FDA bothered by, and how have you addressed it in a sense? You alluded to it earlier. Yeah.
Thank you, Andrew. The FDA letter has now been made public by the FDA of our CRL, and I think we've shared publicly what the three key elements were. The first is that FDA recognizes the unmet need and the patient request and demand for a non-insulin-based therapy to improve glycemic control in type 1 diabetes, because only 20% of patients get the goal. The second is that they realize that they need to be more collaborative with us and expressed a real willingness. Honestly, those words have been matched by their deeds to be very open and quite constructive in their dialogue with us.
The third is their openness of using non-traditional or company-sponsored sort of phase 3 type trial, which was really the significant issue we've had with the FDA throughout is how do you document it with prospective data, the rate of diabetic ketoacidosis, which by its very definition is a rare event. In a group of patients, which is relatively rare with type 1 diabetes, how do you run a study in a reasonable period of time with a reasonable cost, with a clear outcome to meet the FDA's request? I think by FDA's willingness to accept, and as Mike mentioned, and I think we've publicly stated this as the Steno trial, which again is publicly listed on clinical trials, it's a 2,000-patient trial being run by the Steno group and funded through the Novo Foundation, who is their funding source.
Lexicon is not paying for this trial. The trial was already running, so that saved a significant amount of time. We've reduced our cost to essentially just free drug. The timeline significantly, because the trial was already running. To really discuss with FDA the trial design, the way that they are collecting data, the way that they're collecting DKA events, those seem to be acceptable to the agency. Right now, we're really working through the agency on exactly what criteria they want to see in order to satisfy their concern about benefit risk on DKA rates and then the amount of data and exposure data that will be required to meet their test. Will the data actually support the contention that the rates of diabetic ketoacidosis are at or below those that we're seeing in the intended program?
I see. Can you give us a framework of how big of a market opportunity this is, peak sales-wise, if you were to get this approved?
Yeah. This is a pretty sizable market opportunity. There are 1.7 million type 1 diabetics in the U.S. As Craig said, only 20% of them get to goal. There is a huge need for further glycemic control, which they have not had for over a century. It is hard to believe, actually, that that is the case. The important piece for us is that type 1 diabetes offers a different commercial opportunity to what we saw with INPEFA and heart failure. The reason for that is this will be the first and only in its class approved for this particular indication. That affords you a completely different access situation. It affords you the potential to price it very differently to what we saw with INPEFA.
We are very connected with a patient community, with a physician community through our work with type 1 diabetes, through our work with pilavapadin and diabetic neuropathy. We believe that this is a very significant commercial opportunity for Lexicon.
Yeah. I think, Andrew, the other part, again, we in a sense already have a prepaid lifecycle management program as well. I think that's important to remember because in many cases, it's a significant additional expense on the P&L to run a significant LCM. You have the Steno trial running, which is looking at reducing rates of MACE in an enhanced treatment regimen that includes sotagliflozin and/or semaglutide and/or finerenone. I think that will be very helpful. There's a trial that's running a double-blind placebo-controlled study in patients with type 1 diabetes and symptomatic heart failure. That trial is also running and accruing patients and again, is being paid for by third parties. There's another trial that's running as well, type 1 patients with chronic kidney disease and looking at modification of disease progression in that group.
All of that is already ongoing and prepaid. There is also another whole set of studies that are being supported by the NIH that are all using sotagliflozin to look at the mechanism of diabetic ketoacidosis and acidosis in general. All of that work is already paid for and going. I see. Specifically the Steno, because it is open label, you are able to provide the data of DKA rates, whatever the FDA needs in real time.
That's right. Andrew, that's a really critical sort of in-the-weeds point that the fact that it is an open label trial, we can provide, with collaboration with Steno because it's their trial, that data to the agency.
Understood. So meeting with the FDA in Q4, fair to assume we hear back the street in early 2026. Maybe you wait for the meeting minutes. Is that fair? Or could we expect an update actually in Q4?
Look, I think it will be around about that time. We expect to have clarity around the end of this year. We will be either engaging with the street end of this year or early in 2026. Importantly, that would give us the possibility, we believe, to have a potential resubmission early in 2026 as well. Yeah, that is a very near-term opportunity for us.
If the FDA says no, not at this time, we're not yet convinced, do you just stay on the sidelines, wait for these other trials to accumulate more data, then go back to the FDA, or would you consider running a separate trial, for instance?
I think here with the FDA, we are both very aligned on this time around working together in a way where we believe this is an approvable drug. I'm not really anticipating. Of course, we don't know how the data will show out. We know what the data is looking like right now. Of course, we will see as time progresses. I think both the FDA and for Lexicon, we're fully aligned that this is an opportunity that we need to provide folks with type 1 diabetes. Yeah. The two major technical variables are the enrollment in the trial and exposure, and then the rates of DKA that are actually demonstrated in the trial. I think those are really the two main variables.
Right. Right. If this is approved, you mentioned that you could price this differently to INPEFA, which is underlying the same drug. Any kind of color, the pricing differential?
Yeah. It's probably a little premature, Andrew. It's a nice question, but probably a little bit early to comment on that. We've actually conducted some research at the end of last year when we were looking to potentially have an approval. We will sort of double-click on that and confirm our assumptions. We'll probably be able to comment further early next year.
Sure. And then maybe last question, because sotagliflozin has been in the clinic for quite some time. Remind us the patent estate of Zynquista.
Yeah. So we have until 2033.
Okay. Very good. Moving on to HCM, sounds like data could be second half 2026. Is that the case? Phase 3 data?
Again, trial will be enrolled in the first half. Then you got to treat the patients for six months and roll the data up. I think that the number that we've currently publicly communicated is data first quarter 2027.
Okay. Okay.
We are pushing. We are pushing hard to enroll as quickly as possible. Yeah, look, this is an area of high unmet need for the patient and obviously great opportunity. We expect data certainly by Q1 of 2027 and pushing hard to accelerate as much as we can.
My understanding is the primary endpoint is based on the KCCQ symptom score. What kind of data efficacy would you want to see across both obstructive and non-obstructive? What do you deem as successful?
From a regulatory standpoint, I think it's the same thing that is seen as clinically meaningful. Anything greater than a placebo-adjusted improvement of four to five points is seen as sort of a benchmark. I think that's what others in this space have really looked for. I would say that if you look at the recent data that was presented on HFpEF in a placebo-controlled trial in a study called Sotocardia at AHA, there was a double-digit difference in KCCQ. I think there are many that look at HFpEF as a read-through at least for non-obstructive HCM. Those are the numbers that, unlike any of the other drugs that are being looked at in HCM, we have a long track record with, again, over 12,000 patients in heart failure. I think we've got a good understanding of the symptomatic relief.
HCM is just really a subset of HFpEF.
Understood. Would you expect efficacy to look different between non-obstructive and obstructive?
I think if you talk to a lot of the KOLs, and again, all this is speculation, it's unlikely that sota is going to have a dramatic effect on reducing a significant outflow of tract obstruction. I think that there are some that say, "Gee, maybe you'll get a larger reduction." If you have a very large outflow tract obstruction and a large gradient, that non-obstructive could give you a greater improvement than not. Remember, we are allowing patients to be on a CMI as well. As long as the patients have a KCCQ score below 80, that's the inclusion criteria. I think this is going to be really the first data set that's going to have patients on CMIs and also the interesting group of patients who did have an obstruction or are on a CMI and are now non-obstructive but are still symptomatic.
I think that's going to be a really interesting group. We don't know how many people that will be. I think you're going to have every flavor of patient type. I think that's going to be very important data for providers because this will be the first data set that's been done in a high-quality placebo-controlled trial on top of CMIs.
I see. Let's just say this was approved, would this drug be positioned to be used ahead of CMI AIs or afterwards in your view?
Yeah. Look, I think there's a couple of factors that really suggest this could be used first line. The first is that this is a very simple medicine to take. It's a once-a-day oral medicine that has a very well-known safety profile. If the efficacy certainly in non-obstructive turns out anything like we've seen in HFpEF, it will be a very, very compelling proposition to use first line, especially because the Maple data that was read out by Cytokinetics showed that beta blockers at best do nothing and likely are not very helpful in obstructive HCM. It is really causing physicians to rethink the treatment paradigm. sota has a great potential to be used as a first-line agent because of that.
That notwithstanding, of course, one of the issues that CMIs will always have, independent of whether it's MAVR or AFI, is the logistics and the burden that's put in place to initiate and maintain a patient on a CMI. That automatically gravitates towards a later treatment course if a patient is initiated on something and is still symptomatic. We think there's a great opportunity for sota to take a first-line position in both obstructive and non-obstructive HCM.
In the meantime, there is this third-party ISE, SOTA-CROSS, that has data in mid-2026 in non-obstructive HCM. Can you remind us the trial design, how long it is, how many patients, how much read-through could there be from that study to your own study?
Yeah. So again, this is an NIH-sponsored trial being run at the University of Pennsylvania by the same investigator who happens to be one of our co-PIs, Dr. Charlene Day. In terms of patient numbers, relatively small, but the power of the trial is extremely high because it is a crossover design, hence the name SOTA-CROSS. We really are looking at this as the totality of the data. I think SOTA-CROSS is going to provide many of those other metrics that will complement what we're doing in Sonata. What we tried to do in Sonata is to have the most streamlined, most efficient, easiest-to-enroll trial for a registrational study, and then to complement not only with the SOTA-CROSS data, but the SOTA-P-CARDIA data, again, also provides complementary data.
When you look at that, you're going to have genomics, you're going to have proteomics, you're going to have a lot of MRI-based metrics, you're going to have additional physiologic metrics out of SOTA-CROSS and SOTA-P-CARDIA that will then complement the primary endpoint of the KCCQ. Again, high-quality studies that are run across the board.
In the very unusual circumstance where SOTA-CROSS shows a mixed signal, is there any way for you to make adjustments to your own SONATA trial?
My guess is by then, to what Mike was saying before, the trial will be fully enrolled. Again, there's always an opportunity before you close the database that you can change your SAP, but we haven't really thought through that.
Understood. Understood. FDA, however, has given you the green light. One study is enough for FDA approval?
Just like all the other companies. I think you even saw that with the later studies that are done with the CMIs in the non-obstructive that FDA was satisfied with a single trial with a KCCQ primary endpoint.
Okay. So INPEFA, Zynquista, and now this HCM, all rooted on sotagliflozin. Are you filing sNDAs for type 1 diabetes in theory in HCM, or are there unique NDAs? Maybe that helps with pricing differential down the line.
Zynquista is an NDA because that was started before we even did the heart failure program. It goes back a long, long, long way. I think really the opportunity set with INPEFA for HCM, it would probably be an sNDA.
Okay. Thank you. Do you have the intention, let's just say everything worked out, to market this yourselves in the U.S.?
Two different opportunities. I think for Zynquista, we're going to explore everything for the commercialization of Zynquista. We're certainly prepared to take an access-first type of commercialization approach. That then really lends itself to a somewhat sort of flexible model, somewhat virtual, or certainly hybrid model, which we're now getting great experience with our INPEFA sales, actually, which is promoted fully virtually. In addition to that, there's the potential opportunity for co-promotes with companies who are deep in the diabetes and specifically type 1 diabetes space. We're going to explore all of those opportunities. For HCM, certainly in the U.S., I see that very much as a Lexicon opportunity that we would commercialize ourselves. We understand the space very well. We would gear up to drive the commercialization of that ourselves.
Okay. Speaking of commercialization, Mike, maybe I'll just spend a moment since Beatrice was on the agenda today here at your meeting. I think it was notable that that was mentioned repeatedly during their presentation. I think they've been very satisfied. I know we've been very satisfied with them as a partner. They've already filed and gained approval and reimbursement approval in the United Arab Emirates and have filed and/or will be filing in six additional countries this year. That's within one year of signing the deal with them. They've additionally filed in Canada, Australia, and New Zealand, in addition to the UAE, Saudi. They have plans to file before the end of the year in a couple of other markets as well.
Understood. Last couple of minutes shifting to pilavapadin, a novel AAK1 inhibitor.
You mentioned you'll start phase 3 studies hopefully in 2026. Maybe talk about the big picture macro landscape around chronic pain, how that's changed. What's the FDA's view on that compared to before? Is it looking seemingly more favorable, basically?
You know, I think, Andrew, the market has really developed in a very favorable way, even from a policy standpoint. I think there have been two important things outside of Lexicon that have taken place. The first is FDA actually issued a few months ago a draft guidance for running studies in chronic neuropathic pain, which was very much in alignment with our expectations and our dialogue with them. I think FDA recognizes the fact that they put all the effort of putting a draft guidance out and are currently seeking external feedback on that. The other is that there's just legislation that would cover Medicare coverage of chronic pain that's been submitted in the Senate. We believe that there also is a strong push to submit that into the House to have two separate bills.
That would dramatically expand the mandatory coverage, similar to what was done with the No Pain Act in terms of acute pain. In addition to all the work that we're doing, I think there are significant policy supports for this, both from the FDA and from the U.S. House and Senate in terms of the need for non-opiate options.
I see. The macro is definitely on your side right now. You're talking to the FDA about the phase 3 in Q4. When should we hear about an outcome?
I think that would be early in 2026. Once we have the meeting and 30 days later, we should have the minutes. Then we can describe what we've heard.
Maybe last question. Should you start phase 3 studies in 2026, when could we expect data, you think?
I think we haven't talked about that specifically. For PROGRESS, the phase 2b study was a year's time to get that fully completed. Yeah, maybe I'll just give a time frame of the size of the study. We're really looking at probably two parallel trials. There are two arms, so just two-arm trials and roughly 350 patients per arm. You're looking at studies that are not particularly large. To Mike's point, we believe those could be enrolled in about a year. You're looking at a 12-week treatment follow-up. Within a couple of years, you could have data.
Great. I think that's all the time we have. Thank you so much for the update.
Great conversation. Thanks so much.
Thank you, Andrew.