Good morning, everyone, and welcome to our Piper Sandler Healthcare Conference. Really thrilled to be kicking off the first day with Lexicon Pharmaceuticals.
Hey, yes.
Team. Wonderful to have you. We have lots to cover over the next 25 minutes. I think a good place to start off is to just talk about sort of the strategy and the decision that led to reprioritization, which you announced two weeks ago.
Yeah.
So if you could just briefly recap, and what does that mean, secondly, in terms of this reprioritization that's now taking place?
Yeah, pleasure. So in August, we decided to pivot from Inpefa to Zynquista from a commercial perspective. And that was really, as a part of this Lead- to- Succeed strategy, to play where we think we can truly win as a biotech company. And we were all in on Zynquista. We right-sized the field for us to really go down that opportunity. And then our engagement with the FDA around the AdCom had a negative vote.
And we ended up receiving a DRL, which indicates that we are likely to receive a CRL, come December 20th. So with that, it made sense for us to really close down our commercial operations and refocus the company on what we think is an incredible pipeline, particularly with HCM, sotagliflozin in HCM, an upcoming readout of 9211 in diabetic peripheral neuropathic pain, which we're really excited about, and of course 9851 in obesity, so we think we've got a great pipeline and the expertise to execute that, and so that's where we've refocused.
Could you briefly touch upon sort of in terms of the prioritization that how much time or capital is spent across the three programs?
Yeah. From a capital perspective, 9211 has been the biggest lift. But clearly we're at the end of that program now, and are looking forward as to what comes after that Phase IIb program. That has, as you know, many different potential indications. So, making sure that we capitalize on that not only within neuropathic pain, but spasticity as well. The obesity program is pre-IND o r IND enabling studies, it's really not that capital- intensive. And HCM studies being r eally very pragmatic and streamlined. So in fact, it's not taking a huge amount of capital to run that study.
Okay. Perfect. The team would love to spend time on LX9211 as the near-term data i n 1Q. Congratulations on enrollment completion. Really a big lift, right? It's a large study of 416 patients. I guess first question for you is, at what point do you I guess the normal questions on when do we expect will you fine-tune guidance in terms of timing of the data?
Yeah.
Let's start there. And I think you also have publicly said you're gonna host a webinar potentially, in January. Would love to learn what updates you're planning to share it.
Yeah.
At the beginning of the year.
No, absolutely. Let me kick that off. And then, Craig, you can fill in some detail as well. So, you know, we're really incredibly pleased, Yas, with the enrollment in that study. As you know, not only enrolling a good two months ahead of schedule, which is a phenomenal outcome and testament to the trial itself and the investigators, but we over-enrolled by about 20%. So we ended up estimating or powering the study at 416 patients. We closed at 494.
And that has, I think, a lot of implications for the potential outcome in the study. You know, we closed that just recently. And now the last patient will go through their program of eight weeks. And we're aiming to read that out, as you know, in Q1. As we go through into January, we can be a little more specific. But really, we're going to focus and educate, in advance, the public on what we believe that study will achieve, and particularly at that investor event, sometime in January, to really give clear expectations of what the trial will read out.
And the study's enrolling a combination of Type 1 and Type 2 diabetics. I don't know if you guys publicly commented on sort of the distribution of these groups. And secondly, based on the mechanisms, is there any reason to believe that we see differential efficacy in one group versus another? Would love to get your thoughts on it.
Yeah. Yeah. So, what we found in the first trial was very consistent with what you see in the real world. It's about 90%/10%.
Yeah.
90% Type 2, roughly 10% Type 1. We don't believe that there's any reason to think that the mechanism i s going to be any different or the response rates by type of diabetes any different?
Perfect. I think many investors are aware of the big market opportunity and the high unmet med need that exists. But there's also a fear when it comes to execution of pain studies, especially around placebo responses. If you could spend some time talking about learnings from RELIEF and what was incorporated into PROGRESS, that would be really helpful because I think this question will c onsistently come up till the day.
No, absolutely. So again, let me, give a top line and Craig can comment further. I think what you saw in RELIEF is, in fact, the company has a very good control of placebo responses.
Yeah.
If you compare the placebo response from RELIEF from what you see in pregabalin studies and other studies that are currently being run, the placebo response is very low, and that's very deliberate. There's a number of things that in trial decisions allow that, and it's important to have control of placebo. It's important even further to have placebo because without placebo, you can't truly u nderstand what is the drug effect versus placebo, so Craig can talk about some of the things t hat his team and our investigators have really done to make sure that we can control what the placebo response is.
If you look historically at the pregabalin program, which is probably one of the largest programs that was done, if you look across their trials, you have a placebo effect that varies from about 0.7- 2.5 points, and that tremendous variance has a real important impact on the statistics because the greater the variance, then you really have far less confidence in the results that you're seeing. We took two really important steps in the protocol in addition to prescreening the patients. Well, we had a two-week run-in and not a one-week run-in. So you're already lowering the pain score and you're getting less variability in the daily reported pain scores.
If you also look at the underlying DPNP medication, when you take patients off their underlying DPNP medication, not only do you elevate the pain score, but you greatly increase the variance. So by having a third to half of the patients on a DPNP medication, you're also shrinking. That placebo effect and to put it in context, the placebo effect we had in the RELIEF study, the pilot trial that was done that was positive, it was about 0.7. If you look at the historic trials that have been done with pregabalin, the average is about 1.7. So that both you're re-reducing.
The placebo effect and you're reducing the variance, the per patient variability within the study. All of those increase the confidence of your statistics. The downside and one of the issues we've had to explain repeatedly is people say, "Well, your pain reduction is less than the other.
Yeah.
But if you look at the placebo-adjusted reduction in pain score. It's very similar to what you see with 9211 at about 0.7 than what you see historically with pregabalin, which is about 0.7. The baseline adjusted, i f you just compare the patient themselves, is much larger because the placebo effect is much larger.
Very helpful. Team, would love to spend some time on some modifications in PROGRESS versus RELIEF that were incorporated. Maybe worthwhile reminding investors why that was the case. One was you had a loading dose, which you don't have. What was the rationale? That's one. And then two is that the daily pain scores were measured at week six, and you extended it to week eight. So I don't know what the rationale for those two incorporations are. So if you could just remind us, that would be great.
They're related. So, Craig, I'll let you take that one.
Yeah. So the issue regarding the duration is without the loading dose. It takes about two to three weeks to get to the steady-state dose that we believe is effective in neuropathic pain, so when we did the pilot study, you were getting really to therapeutic drug levels on day one. That's really not how normal CNS drugs are used. Certainly not pain drugs where you really with pregabalin or gabapentin, it's a period of two-to-four weeks that you're sort of getting to steady-state. We really took what would be a more traditional approach in the 204 study.
The primary hypothesis we had in this trial, the p rogress trial was to eliminate the dizziness. We believe again, we haven't looked at unblinded data, of course, but the safety profile and dropout rates are dramatically different than what we anticipated because we were mapping. The dizziness on day one to the peak drug level. As Mike said, there are related criteria. By not giving the loading dose, it takes two to three weeks to get to steady-state. Two weeks in the case. Or one week really in the case of the 20-mg dose, two to three weeks in the case of the 10-mg dose, and that's why we also extended the endpoint from six weeks to eight weeks so the patients would have a minimum of six weeks at steady-state.
Okay. Is there an expectation that beyond managing the dizziness, that you could push the efficacy higher too by that additional two weeks too because you're at steady-state or at optimal concentration? Is that or is that too premature to expect like that two weeks could?
We didn't power it based on that. I mean, as you saw in the trial, we're getting efficacy really very quickly.
Yeah. Right.
Within the first week a bove and beyond the placebo effect. Now, whether that's due to that peak drug level or not, that's one of the questions we'll ask. But we believe we've covered that by extending the duration out by another two weeks. However, again, another thing that. The way that we ran the trial statistically, it is intent-to-treat. Many of the other companies that do pain studies l ook at a completers analysis. On an intent-to-treat basis, if you have fewer patients dropping out early, you should have more patients exposed to drug longer. You might expect a larger median reduction in pain score.
Okay. And then teams, just some housekeeping questions. At the top line data, what endpoints will you have on hand to share with investors? And two, I think this will come up quite a bit until the data. What is the bar for success that you would want moving forward to a registrational study?
Yeah. We powered the study similarly with about a 0.65 reduction in pain score. We're using the same statistical methodology that we used in the primary study. We believe we've controlled the Type 1 error. Adequately, you know, at a p of 0.05, again, with a very similar approach that we used to calculate the primary endpoint and the dropout. By having an additional, nearly 80 patients in the trial, that does give us a little more power to assess the primary endpoint. We believe it was already well-powered to do so based on the first study. And with the fewer dropouts that we're now seeing and expecting, the variance of the data should be less. So that, again, also will improve the ability to see the primary endpoint. The primary endpoint is the same.
It is t he reduction in pain score. There are a number of secondary endpoints, which we have incorporated based on the pilot study, really looking at the sleep maintenance, the type of the pain, the burning pain. We incorporate a number of secondary endpoints into this trial that we've learned from the first pilot trial.
Let me just again put a fine point on that, Yas, because it's an incredibly important point here as investors sort of look at the pain space that we've powered it for a 0.6 Placebo-adjusted reduction in pain score. That is, as good or equivalent to what you see with standard of care with pregabalin and if we hit that or greater, this will be i ncredibly clinically meaningful and statistically meaningful result, and will power us through into a complete Phase III program.
Team, I think, could you talk about what do you see on a blinded basis now that the study is fully enrolled, both from an efficacy and safety perspective?
Yeah, so what I can comment again, we look at just the blinded data. Of course. We have had DSMB look at unblinded data, and there have been no issues with the Data Safety Monitoring Board, and they've told us to proceed with the study when we did. We're obviously done and through with that at this point. There's no need to look at the data anymore. The DSMB made that determination as well. What we see is a lower dropout rate. We see far less of the dizziness. You know, the primary hypothesis. We brought into the trial of eliminating.
Yeah.
The loading dose, we achieved that hypothesis.
And then maybe just fine-tune if you could remind me, what do you hope the dropout rate to be at the end of the study?
You know, I would say normally in these trials.
Yeah.
Again, these patients are, you know, unfortunately, h ave a lot of underlying medical conditions. The dropout rates in general are around 10%-15%. Again, I think you have if you look at some other of the historical trials that have been reported, they've actually censored entire sites f or reasons that aren't really clear. But I think we're looking roughly at a 10%-15% dropout rate. We saw roughly a high s ingle-digit dropout rate in the placebo of the pilot trial.
Maybe one last question before we move to sotagliflozin in HCM and then the obesity asset. At the time of the top line data, would you be in a position to also educate the street how you're thinking about into other pain indications? Like, would it be too premature at the end of 1Q to also expect?
Look, look, no, no.
Early developmental.
No, no, no.
Any comments around Phase III design or?
No, we are full steam ahead.
On planning on that, Yas, so we are building out what we believe is the full development program.
We're re-engaging now with the FDA.
To make sure that we can have an end-of-Phase II meeting as expediently as possible. Yeah, we will be moving into the full program, potentially, and we can do that standalone. We think in addition to that, there will be partners who will be engaged in this program. There's clearly quite a lot of interest after RELIEF. There's a lot of interest moving forward as we anticipate the results. We're going full steam, with the complete program. We'll be able to educate the street on what we believe will achieve a broad neuropathic pain label for LX9211, as well as beyond pain into spasticity.
Okay. Perfect. Team, maybe this SONATA-HCM study is PROGRESSing well. Every channel check QR call we do, there's a tremendous enthusiasm for that study. Maybe give us some color on how is enrollment PROGRESSing? When do you hope to achieve completion? Let's just talk briefly about what's been done behind the scenes.
Yeah. Yas, thanks for that question. So we've had several public presentations of the protocol a t the HFSA meeting. While it was virtual, the HCMS meeting as well. We had a number of interactions at AHA, and as. As you've already highlighted based on your checks, the protocol is really seen very, very favorably. It has broad inclusion criteria, minimal requirements for echoes and other follow-ups, the lack of not having the VO2 testing. There's a lot of interest both in the U.S. o utside the U.S. The site openings are going really quite well. You know, a lot of times with academic centers, there's a lot of challenges in opening, and I can tell you that, you know, you have the usual back and forth on budgets. But a lot of the other issues like IRBs and other things, very minimal.
Very minimal issues. We are also getting all of the country approvals o utside the U.S., and those are going on or ahead of schedule around the world, whether it's in Latin America or Europe. So we feel really, really good about it. We've got terrific PIs in the study that are actively engaged in the trial. And really working with us. And I've done a number of site visits myself along with our clinical team. You know, people really are excited by t he trial.
What are you projecting in terms of enrollment timelines?
Yeah. I think we've talked publicly about completing enrollment really by the end of 2026 and data in the first quarter of 2027. Those continue to be our timelines. As always, you know, you wanna be a realist in these things. But, I think there's a lot of interest, and I think there's particularly b y being an add-on on top of the myosin inhibitors, there's an increasing number of patients that are either not getting an adequate response with the myosin inhibitors or where they've been taken off the myosin inhibitors because a lot of these patients. Are having an EF drop below 50. They don't know what to do with these patients.
Okay, and then, team, next year, a lot of investors are tracking the ODYSSEY study, which will be the first registrational study on non-obstructive with KCCQ as the primary endpoint. Which is also your primary endpoint. So could you maybe talk to us about what you foresee? You know, like, is there any? I mean, it's a different mechanism, but is there any learnings that are gonna be derived from that first registrational non-HCM study that could be important to your developmental plan?
I think the real question that I hear in the field is there's a real question of will the CMIs work as well i n non-obstructive as obstructive? I think there's real questions about that, and I think some of the data that have been done i n with the CMIs in HFpEF, which again is m uch closer than with non-obstructive. You know, I think they call into question.
Yeah.
There's a lot of impact on EF. I think there's a real perception that these drugs, the CMIs, are gonna work better in obstructive than non-obstructive, and we believe our mechanism is far more fundamental to the physiology and should work similarly well in obstructive and non-obstructive.
That was gonna come to my next question. Is that based on the pathophysiology of an SGLT1/2? Is there a reason to believe that non-obstructive could? Is it the probability of success equal in both of these two distinct indications, or is there an opportunity it could be used or could work maybe a little higher in one population versus another?
Yeah. I think, again, I'm just gonna say what t he KOLs have said. And again, people are very comfortable doing a trial that has b oth obstructive and non-obstructive in one single trial. Bec ause the underlying mechanism is the same. You know, I think the one of the questions that I hear from KOLs is, "Gee, if there's a large outflow obstruction. Will the SGLT mechanism work equally well as a CMI to sort of increase that, outflow, flow? And I think that's really the question.
I, the sense I get, is there's a high degree of confidence that in non-obstructive, the drug is gonna be really effective. I think we already showed that Based on the subset of the SCORED data , where we showed a 50% reduction in MACE Heart failure. Outcomes, and again, the KOLs really believe that the drug is gonna work similarly well in obstructive and non-obstructive.
I think SGLT2s are being used off-label right now in non-obstructive. Maybe reminding investors, the benefit of a dual SGLT1/2 could be im.
Yeah, so I think, Yas, it's really an important point and we presented some of the data.
Particularly on stroke and MI at the AHA meeting. Also upcoming at the ASH m eeting, which is comparative data that we believe that SGLT1 expression on the platelet, the endothelium, the GI tract. And the myocardium has incremental benefits. And I think you can see that now as we continue to generate data. There was data presented at AHA looking at a model of HCM. Cardiac tissue from University of Penn. That showed a reduction in energetics, which is what you want.
Yeah. In HCM and we showed data that has significant effects in a murine model on clotting. Data that will be presented next Monday at ASH, direct data compared to empagliflozin that shows a reduction in clotting in that same model where sotagliflozin is better. I think, you know, you do see quite a bit of MACE. In patients that have HCM, stroke, and MI, and cardiovascular death in addition to arrhythmias, and we think that that dual mechanism with SGLT1 expression on the myocardium will have benefits across both myocardial and MACE effects like we saw out of that subset of SCORED.
Okay. Perfect. Team, would love to maybe for the next two minutes that's left just talk about LX9851. Maybe just give us an update where you are in terms of IND enabling studies. I think a lot of i nvestors are following.
Yeah. They're PROGRESSing as planned. We still are on track for a submission mid next year.
Okay.
Things are going well with that program.
And given that submission, I mean, the nice part about obesity studies, so you can do short studies and get POC, is there a chance that one could also see first proof of concept human data also next year or next year?
In Phase I? Yeah. No, I think that's, that's the plan.
Okay.
that we'll immediately go to Phase I, and we should be able to see first signal.
Okay.
By the end of next year.
Where are you with your tox package there in terms of the assets? Let's say IND is cleared. You know, would you be at a point where you could run a four-week study, eight-week, or 12-week? Like, you could just 'cause I think a lot of investors usually look for t ime perspective.
Now, we're incredibly pleased with where the asset is in the not only in PROGRESSing the tox studies. The overall IND enabling studies, but also how the readouts are going, as per plans. We are seeing a pretty clear bill of health, as we sit right now.
I think the other important thing always with scaling up is that we have the manufacturing capacity t o run the trials i n humans. And we're doing all of the required work as well on the CMC side t o support, first in human studies and beyond.
Great, well, team, we have come literally to 50.
Wow.
We covered a lot.
Like mad money or something right there.
We covered a lot. Just wanna say thank you. Have a wonderful conference and a phenomenal quarter ahead of us.
Thanks so much, Yas.
Thank you.
Appreciate it. Thank you, Yas.
Okay. Thank you.