Lexicon Pharmaceuticals, Inc. 12th Annual Cantor Fitzgerald Global Healthcare Conference

Yeah. What we've looked to do over the last year or two is really focus the company, and focus our efforts into direct cardiometabolic activity. With that, with our lead program in HCM, we have what we think is a North Star indication really that is going to be a significant contributor to that particular space. In addition to that, we also have a program in type 1 diabetes that's going to be important for us moving forward. Furthermore, also in diabetic peripheral neuropathic pain, which is another important contributor to the pipeline. Finally, in our partnership with Novo Nordisk for LX9851 in obesity, so really a focused cardiometabolic company.

Yeah, Steve, I think one of the things we really try to do is highlight, particularly focused on sotagliflozin for the moment where we have two late-stage programs, is really focus on those areas that highlight the difference in the unique attributes of the dual inhibition of both SGLT1 and SGLT2.

At a highest level, all the life cycle management, all the indications we are going after is really going after those unique indications, such as type 1 diabetes, glycemic control, and cardiomyopathies with a lead in HCM that highlight those distinct attributes that build upon both the long-term history of SGLT2, but really adding where that SGLT1 inhibition makes a difference.

For both of those, really, Steve, what it is about is playing in areas where we feel we can win. Not only from the science, we believe we can show significant differentiation versus standard of care, but importantly, commercially, where we can be the first and only in indication. That provides us a freedom of operation, if you like, to really play in a very significant part within the therapeutic treatment algorithm of these indications, and gives us commercial freedom to provide value to patients and stakeholders.

Well, HCM is a really heterogeneous disease. It is a clinical diagnosis that has a number of etiologies. So we think sotagliflozin on having both SGLT1 and SGLT2, is ideal because you are getting all the benefits of the cardiorenal effects of the SGLT2 inhibition, which are really important in congestion and other attributes of heart failure generally, but the myocardial-specific effects of SGLT1 inhibition as well when it comes to calcium flows, sodium flows, ketone-to-glucose ratios, and a number of other factors related to energetics, which more generally are the underlying pathophysiology of HCM.

Did you want more? Yeah, look, it's interesting, Steve, because before I came to Lexicon, I was involved in heart failure for Novartis for a long period of time.

One of the things is as I operated here in the U.S. in that particular program that was very clear for both Entresto as it was for dapagliflozin and empagliflozin, the pure SGLT2 inhibitors, is that when a patient has systolic dysfunction, so an ejection fraction, certainly HFrEF less than 40, but even between an ejection fraction of 40 to 55 or so, that sort of mid-range ejection fraction, you get efficacy with these agents. But as soon as a patient goes into what we call a normal ejection fraction, so 55, 60, 65, the efficacy of these agents wanes pretty dramatically. So essentially when you have diastolic dysfunction, this big thick left ventricle, these agents are ineffective. That's not the case for sotagliflozin.

Sotagliflozin is the only agent where you see consistency of benefit across the ejection fraction. Most recent data from SOTA-P-CARDIA, as well as some of the post hoc analyses that Craig and the team has done from the heart failure program really shows that sotagliflozin is having a direct impact on diastolic dysfunction, symptoms, and overall structure of the heart, so potentially disease modifying. That was really the first light bulb moment for me to say, "Okay, this is different. This SGLT1 component of sotagliflozin is truly having an impact in diastolic dysfunction," and of course, thereby the direct hypothesis of benefit in HCM.

Absolutely. Well said, Steve, because symptomatic disease with heart failure is associated with congestion, so the blood volume is too large, and because of that, you get pooling of a fluid in the spaces, particularly around the lungs, and it really has a major impact on exercise tolerance, which has a major impact on KCCQ score. We've been able to demonstrate repeatedly in our heart failure program that we have an impact on KCCQ, and that really is a combination that you're getting the benefits of the SGLT2 inhibition. You see those early. You see those within a couple of weeks, and then the longer-term benefits of the SGLT1 inhibition on the myocardium.