Tenax Therapeutics, Inc.

Good afternoon, and welcome to the 10X Therapeutics virtual KOL call. At this time, all participants are in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. A question and answer session will follow the KOL panel discussion. To ask a question, you may press star, then one on your touchtone phone. To withdraw your question, please press star, then two. Please note, today's call is being recorded. I'd now like to turn the call over to Chris Giordano, President and CEO of 10X Therapeutics. Please go ahead.

Thank you, Betsy, and welcome everyone to an in-depth discussion of the science behind 10X's ongoing development program in PHF-PET. We're developing TNX-103, an oral formulation of levocimendin, which we believe has the potential to to be a first-in-class treatment for PHHPAC. TNX103 is currently in late stage development in the phase three level study with top line data expected in the second half of 2026, and also level two, a global phase three study on track to initiate this year. TNX is not alone in focusing on patients with the most common form of PH for which no drug is approved, And it's great to see more and more investigational strategies being evaluated in these patients, considering the grave unmet need that patients with PHFF face. At 10x, we get a lot of questions about the differences between our PHFF program and work done in the space by other researchers. For example, we focus on a different physiologic target than other drugs in development. We have a unique mechanism of action. And aspects of our trial designs are really different to other PHSPF trials, et cetera. So we thought we'd spend an hour today. We thought it would just be good to dig into these differences and explain that these differences are intentional, demonstrate they're grounded in established science and a deep understanding of the disease and of this patient. and hopefully build your understanding of why these differences could be important. Also, we thought it would be good to provide you a viewpoint on these differences from experts outside the company. So before I introduce our speakers today, I'd like to remind everyone that we'll be making forward-looking statements during the event, and please review our disclaimer shown on the slides. Today's discussion will be led by Dr. Stuart Ridge, Chief Medical Officer of 10X. Stuart is joined by Dr. Barry Borlaug, Professor of Medicine and Cardiology at Mayo Clinic, and Dr. Sanjeev Shah, Director of the HFPAF Program at Northwestern University's Feinberg School of Medicine. So Stuart will present viewpoints on these key issues that we face when addressing PHFPAF and then moderate discussions among these experts. before we open the lines at the end of the call for live Q&A. So I'll now hand over to you, Stuart, to begin the panel discussion. And thanks again, everyone, for joining us. Thank you, Chris.

So I'm going to start with the topic of volume overload. The question that we often get is, is it accepted that excessive blood volume in the heart and lungs of patients is a cause of PHF-PEF? So the title of this slide is the title of a paper that was published by Milton Packer, one of the most renowned KOLs in heart failure history. And it's entitled Impaired Systemic Venous Capacitance, the Neglected Mechanism in Patients with Heart Failure and a Preserved Ejection Fraction. This was published in 2020, right after we had published the results of our phase two help study and the assessment of the mechanism of action of levocymendin. And as Dr. Packer points out, it's not something new, it's something that's been neglected. And in the paper when he discussed the dominant phenotypes of patients with this disease, the hypertensive phenotype and the obese phenotype, he acknowledges that venous blood volume is increased in both of the phenotypes. If you're not familiar what we mean when we talk about excessive blood volume in the venous circulation, take a look at this lady's neck vein. It's markedly distended and it's filled with blood. It's almost like a manometer telling you that the pressure in that vein is quite high. The blood volume is so high that it's not only distending her vein, it's overloading the right side of her heart, her lungs, and the left side of her heart at the same time. This is a fundamental problem in HEF-TEF and in PH-HEF-TEF. So to try to explain to you the physiology, if you look on the left side of this slide of a healthy person, you will see at the top there are lungs, then there's the heart, and then there's the splanchnic reservoir. Splanchnic refers to the abdominal organs, which consists of the liver, the spleen, and the small and large intestine. a very large blood supply and actually holds about 30% of all of the blood in your body. It's a reservoir because it's there for when you need it, just like gas in the gas tank of your car. And so when you were sleeping at night, your physiology kind of looks like this. The reservoir is filled, the lungs not so much because you don't need a lot of blood in your lungs to take up oxygen while you're sleeping. If you're one of these people who jogs in the morning when you get up, you need the extra blood volume so that you can run. You get a signal from your sympathetic nervous system to constrict the blood vessels in the splenic reservoir, kind of like squeezing a sponge and getting more water out. That blood will go into your heart and then into your lungs and then into your body with more oxygen. The arrow drawn next to it going in two directions tells you that all day long this is going on in you, depending on what you're doing. There are times when you're resting and the blood volume is in your abdomen, and times when you're running and the blood volume shifts into your heart and lungs. On the right side, however, is an illustration of what happens in patients with PHF-PEF. And here, if you look at the lungs, the lungs are totally full and totally full all the time. The splenic reservoir, however, is constricted and not entirely filled. And this is why you see that lady's neck being so distended because so much blood is coming out of the reservoir into her neck, into her heart and her lungs. And we've drawn this large arrow to show you that it's kind of one way, which means that this is continuous, happening all the time during the day. And thus, our goal is to try to change this abnormal physiology of PHF-PEF and restore it back towards a healthy physiology. So let me stop here and ask our experts what their thoughts are about this mechanism. Sanjeev, why don't you start?