Lexicon Pharmaceuticals, Inc. H.C. Wainwright 28th Annual Global Investment Conference

Well, thanks a lot. Meeting season is well underway here, and we are really happy to be here with H.C. Wainwright this week and appreciate the invitation. Actually, this meeting comes at a very important juncture for Lexicon in our transformation towards a focused cardiometabolic company. Although we have a number of products across the development life cycle, I want to focus, or we want to focus, really on our two late-stage programs for sotagliflozin in two indications where SGLT1 in this dual SGLT1 and 2 inhibitor are really important, and that is in type 1 diabetes, and most particularly, which we will focus on today in hypertrophic cardiomyopathy or HCM.

HCM has become an area of huge interest for investors, for physicians, patients alike as the diagnosis, particularly non-obstructive HCM, increases rapidly and really a therapeutic modality, a nascent therapeutic modality, where there is a lot of potential new treatments, including sotagliflozin moving forward. We are really right at the forefront of this. We will obviously make some forward-looking statements throughout this presentation. Before we dive into HCM, allow me to really recap where we are at in 2026, and we are marching towards achieving our objectives this year. Firstly, for SoTA, as I will refer to it, we have completed enrollment in SONATA-HCM, which is the phase III trial for HCM. I will talk about this in greater depth shortly.

A third-party study, STENO-1, has just completed the recruitment and exposure required in that particular study for SoTA, that will allow us to go back to the FDA with a resubmission in type 1 diabetes. We continue to really drive forward in our partnerships, both with Viatris and Novo Nordisk, which are going exceptionally well. We are currently continuing the dialogue for pilavapadin and AAK1 as a mechanism, where in diabetic peripheral neuropathic pain and in further potential indications where we have some very interesting preclinical data that we will present later this year to really demonstrate the foundational role of AAK1 in human biology. All the while, remaining incredibly operationally disciplined to use our resources in the most appropriate way that provides value to all of our stakeholders.

So let's just dive in a little bit on what has been going on in the company before we get into HCM. Firstly, for sotagliflozin, as I mentioned, we completed enrollment in SONATA-HCM. This is a trial that aimed to enroll 500 patients across obstructive and non-obstructive disease. In fact, we substantially over-enrolled that trial. That was complete at the end of July. It's a 26-week study, which allows us and affords us top-line data in Q1 of 2027. As we go throughout this year, there are a number of interesting and important HCM-focused medical meetings. So once we have the baseline data cleaned, we will look to present some of those baseline demographics at one of those meetings. In type 1 diabetes, Steno-1, a Danish cardiovascular outcome study, has now recruited sufficient sotagliflozin patients with enough exposure.

In fact, exposure resembling what we saw in our total phase III program in TANDEM that was discussed with the FDA that will allow us to resubmit for approval in type 1 diabetes. All along, because this is an open label study, we've been able to observe that the DKA rates in the sotagliflozin group are the same or similar, I should say, to standard of care, and in fact, much less than what was observed in the TANDEM program. So both of those attributes give us strong confidence that we can move forward with a submission in Q4 of this year. Excuse me. For heart failure, Viatris has done an incredible job of submitting and getting approval in the UAE and Bahrain, and those submissions across many ex-U.S. and ex-EU countries continue strongly.

For LX9851, our novel non-incretin mechanism for obesity and related conditions, Novo Nordisk has really taken that program and advanced it very quickly. Lots of enthusiasm around that particular mechanism. In fact, it features quite often in their quarterly earnings. This year we've received three $10 million milestone payments on top of the $45 million that we received last year. Just as a reminder, that deal in total is $1 billion in biobucks. About 50% of those are for clinical milestones, which is obviously going to ramp up as we potentially move into phase II, or they potentially move into phase II with that program, and about 50% in commercial milestones and high single digit to low double digit sales royalties on top of that. So we're super pleased with how that program is progressing.

Finally for pilavapadin, again, a novel small molecule against AAK1, where we have the path forward into phase III for diabetic peripheral neuropathic pain. We've been very diligent throughout this year in rounding out the potential for that mechanism with a number of other indications that we will present publicly a little later this year. But it really demonstrates the foundational nature of AAK1 in a number of human biological processes, really demonstrating the importance of that novel mechanism for which Lexicon Pharmaceuticals is the most advanced company in developing that particular program. So really a lot going on, but like I mentioned, I do want to focus on hypertrophic cardiomyopathy. Let me lead off by saying with top line data in Q1 of next year, clearly we are focused on doing some pre-launch or pre-commercialization activities.

I am pleased to say that Rachael Martin, who has been leading our partnership and strategy function for the last couple of years across Viatris and Novo Nordisk, has been promoted to Chief Commercial Officer. She has got a ton of experience in the cardiometabolic space, particularly in diabetes, having run the insulin business for Sanofi for many, many years. Complementing her, we now have a head of marketing and have just hired a new head of access, and both of these characters are incredibly well qualified and are going to add a ton to the organization. They will really do the pre-launch planning, the market research, the figuring our positioning, and we will start to talk about that in greater detail as we go through this year.

We have also hired five MSLs, which is important as we demonstrate and describe the importance of SGLT1, and why that differentiates from a pure play SGLT2 inhibitor, and how it differentiates from the currently approved CMIs in obstructive disease. Really moving forward at pace. I do want to bring us back down to the foundation in HCM, because I think the community has really been educated around these two distinct entities of obstructive and non-obstructive HCM, when in fact they are not two distinct entities. Just like in heart failure, where there is a continuum of ejection fraction between HFrEF, HFmrEF, and HFpEF, the same happens in obstructive and non-obstructive disease. Truly, at the end of the day, the core problem and core feature that you see in HCM is diastolic dysfunction and left ventricular hypertrophy.

The inability to fill the left ventricle creates a number of downstream issues and number of symptomatic issues as the pressures build up back into the lungs and you get congestion and the like. As we take HCM forward with diastolic dysfunction as being the key driver, we have to recognize that, in fact, the difference between obstructive and non-obstructive is not any difference in disease, it is purely anatomy and where the thickening of the left ventricle primarily takes place. Where in obstructive disease, it takes place higher up close to the valve, thereby creating some obstruction to blood flow, but the underlying diastolic dysfunction is the same, Craig.

Yeah, absolutely, Mike. I think that is really the most important point, is that the disease historically has been defined by the treatment options for surgery and now what I would call a negative inotrope that reduces the contractility of the heart. But the fundamental issue is really the energetics of the heart. sotagliflozin is acting through a number of different mechanisms, which I think matches the heterogeneity of HCM, because HCM is a clinical diagnosis, not a physiologic diagnosis. By acting through the SGLT2 effects, both on the cardiorenal benefit and the decongestion effects of patients with heart failure, and directly on the myocardium to improve energetics, and we have demonstrated that in a number of human genetic studies, in animal model studies, in tissue explant studies, through modifying things like the calcium flux, sodium flux, ketone utilization, fibrosis markers, inflammation markers.

It is acting through a number of different mechanisms to reduce the symptoms, and we've demonstrated in heart failure patients, at least, the long-term outcomes in those patients. Which again, is different than any of the other agents that have either been approved or in therapy that have only been demonstrated in short-term studies to alleviate symptoms.

Yeah, absolutely. With that, we reflect back on SONATA, which is the largest HCM trial across both obstructive and non-obstructive HCM. Over 500 patients, as we mentioned, that significantly over-enrolled, improving the powering of the study. A substantial majority of these patients did have non-obstructive form of the disease, which really reflects current practice. The study sites here have access to CMIs. And obviously with a treatment for obstructive disease, the ability to enroll patients with non-obstructive HCM is more prominent. It's a classic randomized double-blind design, 26-week with a KCCQ endpoint.