Lexicon at Citi’s Biopharma Conference: Strategic Pipeline Insights

On Wednesday, 03 September 2025, Lexicon Pharmaceuticals (NASDAQ:LXRX) presented at Citi’s Biopharma Back to School Conference. The company highlighted its strategic focus on advancing its pipeline, particularly in cardio-renal metabolic diseases. While Lexicon expressed optimism about its innovative therapies, challenges remain in securing partnerships for its pilovapitan program.

Key Takeaways

• Lexicon is preparing to start a Phase 3 trial for pilovapitan in early 2026.
• Sotagliflozin is positioned as a potential first-line treatment for HFpEF and HCM.
• The company is actively seeking a partner for the pilovapitan program.
• Sales of sotagliflozin in PEPFAR markets remain stable.
• Engagement with the FDA continues for Zynquista.

Financial Results

• Sotagliflozin sales in PEPFAR markets have remained consistent year-over-year.
• Ongoing discussions with the FDA regarding Zynquista are continuing.

Operational Updates

• LX9851: Licensed exclusively to Novo Nordisk for obesity and related conditions.
• Pilovapitan: The Phase 2b study in DPNP is complete, with a Phase 3 trial expected to start early next year. The 10mg dose is approved for Phase 3.
• Sotagliflozin: Continued focus on the HCM program with the SONATA trial, expected to complete enrollment in 2026.

Future Outlook

• Pilovapitan Phase 3: The trial design is expected to be finalized at the end of Phase 2 meeting. The anticipated design is a two-arm study with active and placebo groups.
• Sotagliflozin in HCM: The SONATA trial aims to establish sotagliflozin as a first-line treatment for both HFpEF and HCM. Completion of enrollment is targeted for 2026, with data expected in Q1 2027.

Q&A Highlights

• HCM and HFpEF Differentiation: Sotagliflozin’s SGLT1 blocking mechanism is expected to provide benefits in both conditions.
• SONATA Trial: It is the only trial examining both obstructive and non-obstructive HCM.
• Partnership Strategy: Lexicon is in discussions to partner the pilovapitan program, emphasizing the affordability of Phase 3 trials.

In conclusion, Lexicon Pharmaceuticals continues to focus on its strategic initiatives in the cardio-renal metabolic space. Readers are encouraged to refer to the full transcript for more detailed insights.

Full transcript - Citi’s Biopharma Back to School Conference:

Yigal Nochomovitz, Biotech Analyst, Citi: I’ll start. Welcome back, everyone. For those listening in the room and on the webcast, I’m Yigal Nochomovitz, biotech analyst here at Citi. And this is the second day of our biopharma back to school conference. So everyone’s back to school, including the biotech people.

And so it’s my pleasure to have the senior management of Lexicon Pharmaceuticals here with me. I’m Mike Exton, CEO Craig Granowitz, CMO. So thank you both of you, for joining. Appreciate it. Obviously, a lot a lot going on at Lexicon.

The company has evolved a lot. New programs, new data. So, Mike, you want to start, set the scene for us? Yeah. A lot of people just want to hear the basics.

You know, what are the programs and what are the what are the key the key catalysts coming?

Mike Exton, CEO, Lexicon Pharmaceuticals: Yeah. No. Absolutely. It’s it’s been a busy two thirds of the year. And now that the kids are back at school, it’s going to be a very busy back third, I’d say.

So yes, look, it’s been a very interesting year for us as we started the year pivoting back towards a pure R and D company to focus on the pipeline. And as a result of that, we’ve made great progress I believe across the main three assets that we have in the pipeline. And taking them somewhat chronologically, we in the first quarter of the year, we licensed LX9851, which was a preclinical asset for obesity and related conditions. We signed an exclusive worldwide license to Novo Nordisk for that particular asset. We’re delighted to be able to have done that and that they see the value in that asset with, as everyone’s aware, one of the world leaders in obesity, and we can talk a little bit more about that program.

We read out the PROGRESS Phase 2b study in diabetic peripheral neuropathic pain for pilovapitan, a novel non opioid medicine for neuropathic pain as well as other related conditions that we’re also investigating preclinically. We’ve spent the last four, five months really digging into that dataset and looking now across the platform of the Phase two program to see and analyze all of that data moving towards an end of Phase two meeting late this year. And we feel having analyzed all of that data, and we’ll talk about that obviously, that the ten milligram dose is fully endorsed by us and Scientific Advisory Board and others to move into Phase three, which we can start in early next year. Potentially the very first non opioid oral medicine in diabetic peripheral neuropathic pain to be approved in twenty years or so. So that’s an exciting program.

And in fact, now that school’s back, September will be an incredibly busy month of data rollouts at various medical meetings and everyone will get an opportunity to really see eventually the full dataset from the across the platform that gives us confidence moving into Phase three. And last but not least, with sotagliflozin, we continue to sell in PEPFAR in the marketplace for heart failure. And actually, we’re selling about the same this last year with a skeleton resource that’s going very well. For Zynquista, we continue the end of review engagement with the FDA. And perhaps most importantly, certainly coming out of the European Society for Cardiology meeting where there was a lot of great data both from us and others that I think has significant read through to our HCM program hypertrophic cardiomyopathy.

And so that gives us a lot of confidence in the SONARDA trial, which is really enrolling very well, looking for completion of all patient enrollment in 2026. So really a lot of great things to that have been done and a lot more to look forward to over the next quarter or so.

Yigal Nochomovitz, Biotech Analyst, Citi: Okay. Well, let’s maybe let’s start with the cardio, the cardio and HCM considering that was the weekend’s big news And for you had a pooled analysis on SCORED and SOLUS, correct? Can you talk about that? Because obviously, were the heart failure studies, but I’m curious what you drew out of those that new analysis that may be helpful or interesting with regard to HCM?

Mike Exton, CEO, Lexicon Pharmaceuticals: Yes. I’ll let Craig take you through the data for the age breakdown. But not only did we see that data, but also Craig, maybe you can comment on DAPA Act, which was in recent worsening heart failure, which really showed that soda is the medicine premier amongst the SGLT inhibitors for that particular condition.

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Yeah, I’ll start Yigal with the data that we presented as you referenced is that we did an analysis of the pool twelve thousand plus patients in the heart failure program, the recent worsening heart failure and the chronic at risk for patients for heart failure. And what we found was a consistent response across that age group even up to and beyond age 75, which as you know HFpEF is a group largely of more elderly rather than younger patients unlike HFrEF, which is generally five to ten years younger in age of onset. And what we found is that there was a consistent response. The overall risk is higher the older you get, but the relative risk reduction was consistent across all of the age groups that we looked at. I think also importantly, two other key points.

The first is that there was also a consistent reduction in MACE events, which we continually see, which is unique to SOTA in the SGLT class. And the other is that the safety was similar again across all age groups, including even the very elderly in that study. So we thought that this analysis was important on a number of levels as we continue to move into the heart failure space. Mike did mention, and this might be a follow-up question, but I’ll just touch upon it, is that as you know one of the key trials of that meta analysis, the SOLOIST trial, is a trial in recent and worsening heart failure. The population and the endpoints were almost identical to the two thousand plus patient TIMI sponsored trial that was done with dapagliflozin in recent worsening heart failure, which missed its endpoint, showed about a 10 to 15% reduction at sixty days post release from the hospital.

We have a fifty percent reduction in hospital readmission at that time point. So again, and they put this as part of the meta analysis in that study. If you look at the three key trials that have been done in the SGLT class in recent and worsening heart failure, study with empagliflozin called EMPULSE, dabagliflozin called TAPAACT and SOLOIST, we have a fifty percent reduction in hospital readmissions and cardiovascular death at either thirty days, sixty days, or ninety days. And if you look at the data that was presented by the investigators from TIMI, there is no difference in response with the SGLT2 inhibitors at thirty days, And

Yigal Nochomovitz, Biotech Analyst, Citi: at

Craig Granowitz, CMO, Lexicon Pharmaceuticals: the results the the

Yigal Nochomovitz, Biotech Analyst, Citi: ir the I

Craig Granowitz, CMO, Lexicon Pharmaceuticals: I think the trial designs to are actually quite similar. These are stabilized patients with a hospitalization for heart failure. Once they are stabilized and in the hospital, they are then switched over to therapy prior to leaving the hospital. So these groups are all roughly the same in terms of patient characteristics and underlying other medications. I think you touched on it, which is why we continue to be so bullish on our value in HFpEF and in HCM, is that there are direct effects that the SGLT1 blocking mechanism has above and beyond those of the SGLT2 inhibitors because there are also SGLT1 receptors on the myocardium.

And as was in a review article by Gene Braunwald on HCM in New England Journal of Medicine this week, it talks about cardiac energetics, which I think we’ve touched upon a little bit and we expect more data will be coming is that there are unique and differentiated effects of sotagliflozin on the cardiac energetics, is particularly important in HCM.

Yigal Nochomovitz, Biotech Analyst, Citi: Now you I mean, the Scored and the SOLOS data, that’s you’ve had that for some time. I’m just curious on the timing of the pool, this pooled analysis, this was just a new way to look at the data set? Just explain how this happened now versus because I would imagine you had this data for some time or no?

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Well, it’s a great question, Yigal. And I think as we continue to probe more deeply into HFpEF, again going back to the myocardial effects, and as you know that with the SGLT2 inhibitors, the effect size minimizes over ejection fraction as you’re getting close to normal ejection fraction as has been published by with both DAPA and EMPA, there is a mitigation, in fact no benefit at those with higher ejection fractions if you look at KCCQ score, six minute walk test with either EMPA or DAPA. And with SOTA, one of the areas we think again with these SGLT1 effects that we have consistent risk reduction across the entire range of ejection fraction. So as there is a bias towards the more elderly patients and people have asked us about an age effect that we thought this was something that was meaningful and I think ESC felt the same way having it presented as an oral presentation at the meeting.

Mike Exton, CEO, Lexicon Pharmaceuticals: I think as we look at that commercially, maybe this is also a good segue into HCM is for a patient that’s turning up into an office, cardiology office in the community. And that physician is looking at the patient either potentially with HFpEF and or with non obstructive HCM by demonstrating the efficacy of sotagliflozin in HFpEF together with our data that we’ll since see in Sonata in non obstructive HCM. It’s nearly a one stop shop for treatment of either of those patients, which until you do further testing and diagnoses that patient could be presenting with. So it allows a physician, cardiologist to prescribe with confidence a medicine that could be applicable in both disease states.

Yigal Nochomovitz, Biotech Analyst, Citi: It’s a specialized area. I mean, it’s a big area, obviously, a lot of patients, but it’s still specialized and not a lot of even a lot of knowledgeable investors don’t necessarily know exactly the can you just explain the difference HFpEF versus the non obstructive? Like what are the telltale signs of each one? And easily is muddled? And how do you make the differential diagnosis?

Or can it be both? Or how does that how does that all work? So if you

Craig Granowitz, CMO, Lexicon Pharmaceuticals: think about the overall disease, clinically, if you look at a patient, there’s no difference between a non obstructive HCM patient and a HFpEF patient. Right. Right? They present the same way. It’s a person with normal ejection fraction, but has heart failure, symptoms of heart failure, and radiography consistent with that, a big thick left ventricle.

So those are, in a sense from a clinical standpoint, grossly the same disease. Right? It’s sort

Mike Exton, CEO, Lexicon Pharmaceuticals: of like

Yigal Nochomovitz, Biotech Analyst, Citi: So there’s reason to confused sometimes. Okay.

Mike Exton, CEO, Lexicon Pharmaceuticals: Sure. Yeah. Absolutely. And I

Craig Granowitz, CMO, Lexicon Pharmaceuticals: think one of the reasons why there’s been such a dramatic under diagnosis of non obstructive HCM is unlike obstructive HCM where you see a big outflow tract obstruction and you have a large gradient across the aortic outflow, is in non obstructive it’s not so easy to tell. I think there are a number of diagnostic criteria that are becoming more aware, particularly if you look at EKGs and you do more sophisticated testing looking at cardiac energetics, there are genetic diseases that are associated with HCM, particularly the overactivity of the actin and myosin that you don’t see in sort of run of the mill HFpEF. But the first reason why we started looking at HCM is we did an analysis of those patients that had HFpEF, had left ventricular hypertrophy without hypertension. Because the major reason why people have left ventricular hypertrophy in The United States and Europe is due to hypertension. Right?

The heart is pumping against this big pressure gradient for decades and the heart gets thicker. And as the heart gets thicker eventually it gets so thick it outruns its blood supply and you end up with heart failure. So if you exclude the patients with hypertension, that group is enriched for a group that looks very much and probably had occult HCM in it in our own clinical heart failure program. We saw a fifty percent reduction in heart failure events and MACE in that subgroup we’ve published. That subgroup was about five hundred patients.

That was when we started really looking seriously about soda as a unique agent in the SGLT class for

Mike Exton, CEO, Lexicon Pharmaceuticals: HCM. Collectively, Gal, again, just to sort of bring this back strategically where we’re seeing it. Because as you said, we’ve had the SCORDS and SOLARWIS data for a long time. We’ve looked to launch that in heart failure against the SGLT class in general, which makes it difficult from a payer perspective. But as we look forward to HCM being hopefully positive with the SONARTA trial, there’s a real opportunity for us particularly in HFpEF for sotagliflozin to be the drug of choice, the first drug of choice for both HFpEF and HCM for which clinically as Craig said, essentially a community cardiologists sees them present as exactly the same.

They can use this medicine because it’s safe, it’s well known and it’s efficacious and more efficacious than other SGLTs in the class.

Yigal Nochomovitz, Biotech Analyst, Citi: Okay. Well, that’s a good a very good review of the landscape. Can we just go through then just the mechanics of the SONNATA trial? What exactly are the endpoints? When what is the progress of the study?

You said I think it’s reading out by next year?

Mike Exton, CEO, Lexicon Pharmaceuticals: We’ll finish enrollment next year. Next year, okay. But maybe, Yigal, if you don’t mind, before we get to Sonata, it’s worthwhile touching on Maple and that read out at ASC. Odyssey was from Bristol Myers, which was the very first readout of a trial in non obstructive HCM as you know mavacamten or KANZYSIS indicated in obstructive because it reduces the outflow tract obstruction as Craig said. And I’ll let Craig describe the study and the outcome.

And then the other one was MAPLE, which was a study of aficamten from Cytokinetics where it compared africanctin versus a beta blocker, which is the typical first line agent in HCM. In this case, it was in obstructive HCM. And both of those sets of data I think have incredibly useful read throughs to the HCM program for sotagliflozin in Sonata. So maybe let us touch on that date first and then we’ll move into the mechanics of Sonata.

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Yeah. So thank you for the question Yigal. And the OHDICEY trial was very important because it was the first CMI readout in non obstructive HCM. And it did not hit either of its is really the primary endpoint. And they split the alpha, I don’t want to get into too many technical details statistically, but they put most of the weighting of the endpoint on the KCCQ and they missed on both those endpoints.

So there’s a question of will the class of CMIs work as well in non obstructive HCM as they do in obstructive HCM? Because I sort of look at the CMIs as kind of a medical septal reduction surgery, right? They are very effective, both AFI and MAVA at lowering the outflow tract obstruction in obstructive HCM. The issue is though that the underlying disease process, and this gets to why our trial design is what it is, the underlying dysfunction between obstructive and non obstructive HCM on the myocardium in the heart muscle itself is similar. And we believe that sotagliflozin and uniquely sotagliflozin in the SGLT class and very differently than CMIs are working to address that metabolic disorder of the myocardium in HCM.

That is the unifying hypothesis in HCM which is the fundamental physiologic problem. And you see that because if you do septal reduction therapy in symptomatic HCM patients, ten percent to twenty percent of those patients within a few years go on to develop heart failure. So they are converted from an obstructive HCM patient to a non obstructive HCM patient. And again, one of the reasons we have the quality of investigators and the interest in the field is that we are addressing that underlying fundamental pathophysiology. So that’s sort of the ODYSSEY trial.

The MAPLE trial

Yigal Nochomovitz, Biotech Analyst, Citi: So just to clarify, so this this have we had a CMI ever work in non HCM? Or that’s never

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Non obstructive. Non obstructive. Non in a large randomized controlled trial. OHDSI was the first and it was not successful. There’s a trial that is being run right now by Cytokinetics called Acacia, which is fully enrolled and I think as you heard or your listeners heard yesterday from Cytokinetics that that trial I believe will be reading or finishing next year.

Yigal Nochomovitz, Biotech Analyst, Citi: Okay. Okay. Now, then you want to talk about MAPLE?

Craig Granowitz, CMO, Lexicon Pharmaceuticals: So MAPLE I think is a very important study and Mike and I were talking about this. I think we didn’t realize just how meaningful it was to the field because what it was was a first line therapy, of a CMI, in this case, aficantin against a beta blocker. And beta blockers have been used for decades, really since beta blockers and HCM were identified without much clinical evidence to support their use. I think one of the takeaways from Maple, as much as aficamtan was successful, it also highlighted that beta blockers might actually cause harm. The baseline after the patients were on a beta blocker for the duration of the study.

So not only did aficamtan improve many of the endpoints, but that the beta blocker actually the endpoints were worse at the end of the trial than the beginning.

Mike Exton, CEO, Lexicon Pharmaceuticals: And so one could conclude from that data that potentially aficantin could be used as a first line agent in obstructive HCM. That is practically unlikely, mainly because of cost, access, the logistics involved in getting a patient on and maintaining them on a CMI. And so our take home for sotagliflozin is that in fact beta blockers potentially cause harm. They’re the go to first line agent in HCM. And now there’ll be a rethink in the cardiac community.

And in fact, SODA is well positioned to be that first line treatment so long as Sonata is positive with following use of the CMI should it be needed for worsening or more symptomatic HCM further down the track. So really positioned Soda to take that first line therapy option in both obstructive and non obstructive HCM.

Yigal Nochomovitz, Biotech Analyst, Citi: So the point of Maple is that because you were running the beta blocker versus the novel therapy, this exposed the weakness of the beta blocker because you just didn’t have a randomized study to do this before. Is that correct?

Mike Exton, CEO, Lexicon Pharmaceuticals: Exactly. No one who was going

Craig Granowitz, CMO, Lexicon Pharmaceuticals: to run that trial, right?

Yigal Nochomovitz, Biotech Analyst, Citi: So this was sort of unintended consequence.

Mike Exton, CEO, Lexicon Pharmaceuticals: It’s been in a way just a natural thing for clinicians to do. Beta blockers are very effective medicines for a range of different conditions and so it made sense for them to try it, but without any evidence. And now really for the first time and kudos to Saito for running this study, it really showed that that is a false assumption. And they need

Yigal Nochomovitz, Biotech Analyst, Citi: to rethink Not to distract too much from the Lexicon discussion, but in this in in Maple, so did the study work because AFI worked or because beta blockers failed?

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Both. Both. Yeah. So again, if so the issue is if you compare to baseline, AFI was successful in their endpoints. And again, I don’t want to overspeak for Yeah.

Cytokines, but the beta blocker also was worse. So when you look at compared to the active arm, it made the results look even better. Yeah. Okay. Alright.

So that brings us to your study. So that so I think long long wind up for

Yigal Nochomovitz, Biotech Analyst, Citi: the pitch. I’m looking for the clock. I have to get

Craig Granowitz, CMO, Lexicon Pharmaceuticals: to Wait. Wait. We’ve time. But I think that’s that’s really highlights your original question way back when on the importance of the trial design of our study, the SANOTA HCM trial. I think there are this all this background is very important because we thought about this as we designed the trial.

So there’s a number of very different attributes in the trial design. The first is that it is the only trial that’s looked at both obstructive and non obstructive in the same trial. And the primary endpoint of KCCQ, which is symptom relief, which is really what the CMIs are approved for symptom relief is the primary endpoint in the trial. And by including both obstructive and non obstructive, we believe since the fundamental mechanism underlying the both is the same, that’s why we put them together, just like we are the first to do in heart failure, a HFrEF and a HFpEF study together in the same trial. So that’s one attribute.

The second is, as I think you’re aware, is that one of the big concerns with CMIs is potentially causing heart failure. That the major issue and the reason for the REMS is that EFs dropped below 50%. And that was clearly a major problem in the OHDICEY trial for BMS is twenty percent of the patients had an EF drop below fifty. We are allowing patients

Yigal Nochomovitz, Biotech Analyst, Citi: That’s interesting. What’s the reason? I mean, because I thought the whole idea was improving the microtubule contractility. Right? Well, actually, it’s

Craig Granowitz, CMO, Lexicon Pharmaceuticals: the opposite. It is reducing the force of the over contractility. So the whole idea is correcting over contractility. And again, I don’t wanna speak for those that are expert in this area, but my understanding is that one of the issues is that you are in a sense making the actin and myosin less overactive than the disease state causes. And the underlying pathophysiology and the way that the CMIs are working is they are working to change the interaction between actin and myosin, which results in excessive oxygen consumption.

In fact, most early patients with HCM have an over dynamic ejection fraction. The heart is too active. Okay. The flip side of that is that in a percentage of patients you actually have their ejection fraction drop below 50. So in a sense, we’re an agent and we’re indicated to prevent and reduce heart failure.

These are agents that the REMS are put in place because they result in heart failure. So we also, in our entry criteria, if the patient’s not on a CMI, and I’ll get to that in a minute, the ejection fraction inclusion criteria is 50%. The CMIs are at 60. If the patient is on a CMI and we allow patients to be on CMIs, that inclusion criteria is 55%. But again, we are allowing patients in the trial with a lower baseline EF than the CMIs because we don’t have a heart failure issue with our drug.

We prevent heart failure. The third point I already touched upon is that we’re allowing any patient on any therapy that has symptomatic heart failure by KCCQ at baseline. So they can be on

Yigal Nochomovitz, Biotech Analyst, Citi: a beta blocker, they can be on

Craig Granowitz, CMO, Lexicon Pharmaceuticals: a calcium channel blocker, they can be on disoperamide, they can be on a CMI. They can be on any of those therapies. The key inclusion criteria is a diagnosis of HCM whether obstructive or non obstructive and have a KCCQ score below 85. That’s it. The other important point during the therapy, for example, if you look at a trial like Acacia, there are about nine echos that need to be done during that treatment.

We have three. So again, the burden of monitoring, the burden of the endpoint is far different than the CMI trials have been and are currently running.

Yigal Nochomovitz, Biotech Analyst, Citi: So there are a lot of moving parts to the study because you’ve got the obstructive, the non obstructive, you’ve got whether they’re on the CMI, not on the CMI. I guess there’s some stratification, so it’s all balanced out. And then like how do you win? I mean, you can win on everything. Do you have sub analysis?

So if you hit it on the HCM, it’s one. If you can get a label, if you hit it on non, it’s a label. Like what is the hierarchy of analysis? How much of

Craig Granowitz, CMO, Lexicon Pharmaceuticals: that have you talked about publicly? I don’t know. We haven’t discussed a lot. I mean, we have talked about the fact that the endpoint is powered for the overall group. Again, just go back to what we did with SOLOIST in heart failure.

So what the FDA generally does, and they did in the case of SOLOIST, is the study and what we’ve agreed with the FDA already, because we did go down to the agency before we started this trial and we agreed on endpoints and statistical methodology statistical analysis plan is that the study is powered for the overall group, and the patients are randomized one to one. So it’s two fifty patients with obstructive, two fifty patients with non obstructive in the trial. The study is powered based on the overall result. We will look at an interaction p value between obstructive and non obstructive. But as I’ve said, and I think we feel very confident about this based on our interactions with the KOLs, since we’re addressing an underlying physiologic issue, there probably is not going to be a major effect effect size based on whether they’re obstructive or non obstructive.

And the comparison is what? Placebo. Placebo.

Yigal Nochomovitz, Biotech Analyst, Citi: Okay. And so that was there just a thought that you would do beta blockers or

Craig Granowitz, CMO, Lexicon Pharmaceuticals: that was never Remember beta blockers are we’re allowing them to be on or not on.

Yigal Nochomovitz, Biotech Analyst, Citi: Oh, so they’re on them in the background on both sides?

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Correct. Beta blockers, calcium channel blockers or CMI. Remember the key inclusion criteria is symptomatic disease, whatever their underlying therapy, right? We’re just enrolling patients based on symptoms.

Yigal Nochomovitz, Biotech Analyst, Citi: Then once they’re obviously, once they’re enrolled, I mean, then they must stay on their whatever background they’re on, they’re forced to stay on.

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Yeah, there are certainly elements in the protocol because with data

Mike Exton, CEO, Lexicon Pharmaceuticals: yet in the enrollment. But I wouldn’t expect too many patients in Zonata to be on a CMI. The penetration is relatively small so far in mavacamten. So we’ll certainly see patients with background beta blocker calcium channel blockers. Maybe we get CMIs, but I wouldn’t necessarily predict that there’d be a massive group that Based is on same

Yigal Nochomovitz, Biotech Analyst, Citi: on the results of Maple, which I didn’t know until you because I hadn’t looked at it closely, but you would want more people on a beta blocker in the control arm. I mean Maybe why they’re symptomatic.

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Yeah. So They’re effectively all on beta blockers, Yigal. I mean, that’s sort of like

Yigal Nochomovitz, Biotech Analyst, Citi: That’s how

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Every patient that comes in, they’re on a beta blocker. I I I again, I don’t know exactly what the numbers are, but my guess is eighty percent to ninety percent or more will be on a beta blocker. Now that might change over time, but I think that will take some time to diffuse into the field of changing medical practice to not put patients on beta blockers, especially outside The United States.

Yigal Nochomovitz, Biotech Analyst, Citi: Okay. So just one more on HCM.

Craig Granowitz, CMO, Lexicon Pharmaceuticals: So your enrolling is finishing next year and then data is when? Well, again, one of the advantage of this is it’s a relatively short study with a relatively short follow-up. Unlike the CMIs where these are new agents in a totally new class and they have a long follow-up period, we don’t need to do that because these are proven drugs that are already indicated and on the market. So we will have data, I think we’ve talked about ’27. Okay.

For the KCC? Q1. Okay.

Yigal Nochomovitz, Biotech Analyst, Citi: All right. At that point, I guess, would you know the outcome? I guess that’s a Cyclinetics question, they would they know

Craig Granowitz, CMO, Lexicon Pharmaceuticals: the outcome of Acacia by then? From what they’ve said, yes. Okay. Right. Let’s shift gears then.

Rapid fire.

Yigal Nochomovitz, Biotech Analyst, Citi: There was some discussion around ten or twenty. Right? And then you picked ten. Yeah. So so and and you have the end of phase two meeting or that’s coming up?

Mike Exton, CEO, Lexicon Pharmaceuticals: It it’ll be at the end of the year.

Yigal Nochomovitz, Biotech Analyst, Citi: It’s coming

Mike Exton, CEO, Lexicon Pharmaceuticals: up. And what do you

Yigal Nochomovitz, Biotech Analyst, Citi: what do you want to lock down in that meeting?

Mike Exton, CEO, Lexicon Pharmaceuticals: We want to lock down the design for Phase three and the dosing, which as we said, we feel very good about. We’re just getting into the final throes of putting all the information together right now for submission to the FDA. So it’s really the clinical design of the Phase III program that’s important. The dose ensuring, as we’ve said before, that we believe single arm, single active, single placebo study. So two arms in each Phase three study is the way to go.

And we just need that confirmed by the FDA.

Yigal Nochomovitz, Biotech Analyst, Citi: So you mean two identicals?

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Does Yes. It We’ve already had a pretty thorough meeting with the FDA before we started the PROGRESS trial, which is now completed. And I think what we’ve seen with a couple other companies that are also now trying to work in the pain space, You need two well designed trials that are run-in this area with a positive outcome. We believe based on the effect size and the variance of the data that about three fifty patients per group, so 700 patients in a two arm study, and two of those trials run-in parallel would be adequate for approval. We’ve heard that from the FDA and I think we’ve seen other companies now talking about Phase three programs in neuropathic pain and they came to the same conclusion in that regard.

So we feel quite good about the design, the size, the powering, because remember we have three studies that we’ve run-in Phase II with pilavapitan in different neuropathic pain states. And we have now a very good understanding with well over seven hundred patients treated, over six fifty of which were in DPMP and another fifty or so that were treated with PHN, that we have a good understanding of this drug and the population PK in terms of exposure and response. So we have a very large Phase II database on this molecule. I think we want to reaffirm with the FDA our assumptions going in, the dose, the size of the trials, the number of trials, and then all of the other studies that FDA would like to see that would support the registration. And there are a number of trials we’ve already run that are non pivotal trials, but very important for final approval and labeling and just want to reaffirm that with the agency.

Yigal Nochomovitz, Biotech Analyst, Citi: I mean, doesn’t sound like to me, it sounds like that should be fairly clear and straightforward essentially with this. I mean, it’s done you’re not proposing anything too far afield. Right? I mean, it’s just for versus placebo, two studies, while you’ve done the powering calculations, it’s just more do do you expect any pushback from them?

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Or is it just I mean, think the value of having run two Phase II studies and then having the PHN study and then all the other data we’ve run is that a lot of the questions I think have already been addressed. Running pain studies is hard enough. There are enough variables, particularly the placebo effect is a huge issue in this. The issue around concurrent medications is a big issue in this patient adherence, the PRO endpoint. So one of the approaches we took was the more that we could do in Phase II to simplify the design, simplify the primary endpoint, the better.

Because when you add arms and you add complexity of endpoints, you increase variability and questions. So we did a thorough Phase two program compared to what has been done historically in the pain space. We did that specifically to reduce some of the variability and some of the questions that you would have going into a Phase III discussion or pre Phase III discussion with the FDA.

Yigal Nochomovitz, Biotech Analyst, Citi: Or did you consider any of these you know, crossover designs where you switch and you put the Pila patients on placebo and placebo on Pila at the end? And that I mean, that can that nothing it it sounds more complex, but it’s not necessarily because actually it can increase the power in terms of

Craig Granowitz, CMO, Lexicon Pharmaceuticals: this the crossover. So I think those are great studies for phase two. I think a variation of that, which some people do if they’re worried about rebound effects, is to do sort of a withdrawal type study where you have a response and do a blinded withdrawal study. We don’t feel that either one of those is relevant, right? We already have two studies where we had a blinded runoff period.

And I think very importantly, we saw there was no sort of liking potential for the drug. In all these drugs essentially acting agents, there’s an issue of potential addiction potential. There’s also an issue of rebound pain, is commonly seen in this, in part due because many the other drugs have very short half lives. So we have now demonstrated that there are neither of those in our blinded runoff period. So that the necessity for looking at off drug effects, and we’ve also demonstrated and we presented on the relief trial, the first phase two trial, that the benefits of this drug persist for weeks after you stop dosing.

Certainly because of the long half life, but maybe we’re beginning to do some rewiring of the pain circuitry as well. I mean, I think that’s purely speculative on my part. But as you know, neuropathic pain is both an issue of physiology and psychology. Pain is very much a learned and reinforced behavior with people. I’m not saying that in any pejorative way, it’s just that when you establish the circuits of pain, you have to rewire the brain with chronic pain to minimize some of that pain state.

Okay.

Yigal Nochomovitz, Biotech Analyst, Citi: And then the so if you would if you get these numbers that you got in Phase two, the 1.7 or thereabouts and the 1.3 that would be that would work that would win, right? If you got those numbers again with your powering, you’d be in good shape.

Craig Granowitz, CMO, Lexicon Pharmaceuticals: That would be a statistically significant difference. I think there’s a drug that was just recently approved in a pain state for chronic fatigue syndrome that basically that was what they achieved and they were labeled.

Mike Exton, CEO, Lexicon Pharmaceuticals: Okay. With two studies. Yeah. With two studies.

Yigal Nochomovitz, Biotech Analyst, Citi: Right. Okay. And those are well, so you get the sign off from the FDA later in the year. And I guess this is more of like a financing question, but do you have the capital to do these studies? Because these are not 1,400 patients, I think.

Right?

Mike Exton, CEO, Lexicon Pharmaceuticals: No. Right. The phase three trials are relatively inexpensive because they’re short duration and there’s not a lot of fancy testing, etcetera. They’re relatively inexpensive. Having said that, it’s our intention to partner this program and we’ve we’re deep into that process at the moment working towards the end of Phase two meeting, which will obviously be important for some potential partners to get the outcome of that meeting even though as you said it is pretty straightforward having the outcome confirmed post meeting could be important for some partners.

And we’re really focused on finding as we did for 09/1951 the best partner that not only can bring the potential pain program forward and invest in the Phase III program, but importantly look at the overall expansion of potential indications across not only indications in neuropathic pain, but spasticity, potentially there’s other neuroscience types of indications for which we have some preclinical data and making sure we take advantage of the breadth of the implication of AKI-one.

Yigal Nochomovitz, Biotech Analyst, Citi: And you’re looking for what type of deal? I mean, it like a region specific deal or something multi net like

Mike Exton, CEO, Lexicon Pharmaceuticals: multi No, think it will be worldwide. I think there’s various options as to the depth of involvement of Lexicon depending on who the partner could be. I think the most important thing that we’re focused on now is like as we’ve seen with both Nova and with Beatrice, In each case, these partners are fully invested and believing in the mechanism and want to do a very significant broad program in both of those cases. So I think we’re a little bit agnostic to the type of player and indeed we’re talking to different types of players on different scales, but it’s making sure that we truly have someone that’s invested in this program for the long term.

Yigal Nochomovitz, Biotech Analyst, Citi: All right, awesome. All right, well, great. Thank you both very much. We look forward to, you know, finishing the enrollment and then be a little while for the data, but certainly, it’d be very exciting to see that.

Mike Exton, CEO, Lexicon Pharmaceuticals: Great, Igor. If if I could just sort of finally point everyone’s attention to the Arrowhead meeting, which is at the October, I believe, which we obviously have a number of data readouts and presentations at medical meetings in September. The Arrowhead meeting is the one where we will really cover the breadth of the data across all of our Phase two program. And I think that will really form the basis that people will see as we take into the end of Phase two meeting.

Yigal Nochomovitz, Biotech Analyst, Citi: That’s a medical meeting. And where

Mike Exton, CEO, Lexicon Pharmaceuticals: is that? San Diego.

Yigal Nochomovitz, Biotech Analyst, Citi: Okay. And that’s a neuro meeting. What exactly what type of meeting is it?

Mike Exton, CEO, Lexicon Pharmaceuticals: Yeah. It’s a pain meeting. Pain minutes. Okay.

Yigal Nochomovitz, Biotech Analyst, Citi: Excellent. Thank you.

Mike Exton, CEO, Lexicon Pharmaceuticals: Great. Alright. Thanks so much. Appreciate it, Yigal.

Craig Granowitz, CMO, Lexicon Pharmaceuticals: Okay. Thank you. Thank Yigal.

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