Good morning, everyone. Thank you for joining the H.C. Wainwright 28th Annual Global Investment Conference. My name is Emily Bodnar, and I am an equity research analyst at H.C. Wainwright. I am pleased to be doing a fireside chat with Thomas Strack, Chief Medical Officer, and Michael Tung, Chief Financial Officer of vTv Therapeutics. To start, for those who are not so familiar with vTv, can you give us a brief introduction to the company and walk us through some of the recent pipeline? Yeah. Sure. I will kick it off. Emily, thank you so much for the invitation. It is good to be back. Really appreciate you inviting us. So vTv is a publicly listed, late-stage clinical biopharma company. Our lead asset is a drug called cadisegliatin, or CADI for short, which is basically being studied in phase III for the treatment of type one diabetes. Type one diabetes impacts 1.5 million people in the U.S., and 75% of the 1.5 million people living with T1D do not get to hemoglobin A1c of seven or below, which is the recommended target that the American Diabetes Association recommends. There has been nothing new on the adjunctive treatment side for type one diabetics in over a century, when insulin was first discovered. So there is a massive unmet medical need out there. We have an experienced leadership team. We have guided to completing enrollment of our phase III CATT1 trial in the third quarter, so stay tuned in the coming weeks, and that would lead to a readout of the top line data in 2027. On the financial side, we are well-financed through that top line data. That is a quick summary on the company. Awesome. So CADI is a glucokinase activator, or GKA. Can you walk us through a bit about the mechanism of action of GKAs and how they are implicated in type one diabetes? Yeah. Glad to do that. Glucokinase is really an important enzyme in our body. It is expressed in many tissues. Its most prominent function in most tissues outside the liver is just to sense the amount of glucose that is circulating and directing the host cells, if you like, to then adjust their secretion patterns of hormones in the pancreas. Insulin expressing cells, the beta cells, as well as glucagon expressing cells, the alpha cells, determine their secretion of glucagon and insulin based on glucokinase signals, basically telling them how much glucose is out there. One important organ in our body is the liver, often overlooked. In people with type one diabetes, that organ does not fully function because the glucokinase in the liver is dependent on exposure to insulin. As you all know, in type one diabetes, beta cells no longer secrete insulin. With the drop in insulin exposure, which cannot be fully replaced with exogenous insulin injections, the glucokinase levels drop, and thus the liver is impaired to really take care of business when it comes to managing glucose. The liver is really important in this sense because glucokinase is much higher, much more expressed in the liver, and that is because it is not only a sensor there, it is also a trench worker. It basically helps the liver to keep glucose that rises after meals in the organ, and a good part of that is being transformed to glycogen. The liver stores about one third of the body's glycogen reserves, which are required when you experience low blood glucose levels, and so the liver is being told, "Now we need to replenish glucose levels." So it is a really critical organ to maintain normal glucose metabolism. Yeah. GKAs have been de-risked in development for type 2 diabetes. There has been several approvals ex-U.S. How does the mechanism differ in type one versus type two? Given you talked about the liver, how does CADI's liver selective design differ from some of the prior agents? All glucokinase activators, literally as the word implies, work by activating glucokinase. They bind to the glucokinase molecule and they make it work a bit harder, so it basically can process more glucose than it normally would do. In the past, glucokinase activators were non-selective. They were activating glucokinase in the pancreas, in other organs, and of course, in the liver as well. Also initially, glucokinase activators were almost exclusively developed for type two diabetes patients. The problem with that is that in the pancreas, on the beta cells, glucokinase activators were working basically like any other secretagogue. It was turning on insulin secretion, but it was not glucose regulated, so people actually experienced hypoglycemia. In the liver, the same happened because it was also often these activators were interfering with what is exclusive to the liver. There is a feedback mechanism that up or down regulates glucokinase activity. When molecules like glucokinase activators interfere with that, it can be turned on permanently, and again, it leads to potentially hypoglycemia, but also to overproduction of fat, because once the liver is full of glycogen, it switches to actually storing fat. That's the reason why many of the early generation glucokinase activators did not work really well, especially not long term. You get some loss of activity because the pancreas is being stimulated again and again. Basically the same things that you see with sulfonylureas. Cadisegliatin is very different because, having learned from the sort of negative experiences, the design was to focus on the liver as the target organ to take advantage of the kind of feedback that you have in that organ only, and also, of course, because the liver has much more impact due to its capacity to, independent from insulin actually, absorb glucose and store it as glycogen. Cadisegliatin is designed to bind to very specific molecules on the liver cell, which is also used by other medicines, and that makes it liver selective. It will not bind outside the liver. Maybe talk a bit about your Simplici-T1 trial, which showed positive results in type one diabetes patients. What was the data that you demonstrated on hypoglycemia improvement and HbA1c reduction there? Yeah. Simplici-T1 was a phase II study, double-blind, randomized, placebo-controlled trial in patients with type 1 diabetes, and was a treat-to-target study. Patients were instructed to lower their glucose as much as possible to which ADA targets of good control. Most patients had CGM sensors. Some also had pumps. The study was conducted at a time in 2018 when maybe only half of patients usually in trials had pumps or CGM sensors. The key outcome was we could lower HbA1c, which was important, but I think more importantly, we actually noticed that the rate of hypoglycemia was reduced by 50%. Ultimately, FDA felt that it was a really important finding, leading us to receive breakthrough therapy status. Yeah. How clinically meaningful is that 50% improvement in hypoglycemia, and are you seeing broad efficacy across patients that you've looked at? Yeah. Probably actually prior to doing the type 1 diabetes studies, we conducted a few studies in type two diabetes. Cadisegliatin was very much able to lower HbA1c by up to 1% in a six-month trial, and with no hypoglycemia as a risk, nor any other adverse effects apart from lipid metabolism. Lowering hypoglycemia in type one diabetes is really critical because a lot of people still experience hypoglycemia on an almost daily level, despite advanced technologies such as closed-loop systems. Insulin has a very narrow therapeutic index and a lot of variables that are really hard to control for an individual patient. This is an ongoing problem. Some people end up in the hospital because they have significant hypoglycemia, impairing them to the extent that they are no longer conscious. They cannot treat themselves. That persists even with that technology. Clearly, it's an ongoing significant unmet need. Talk to us a bit about the safety profile of CADI. Also in your trials, you've had an absence of diabetic ketoacidosis. How important is that for potential approval as well? Yeah, it's a principle concern. For example, European Medicines Agency requires diabetic ketoacidosis data at the time of submission for approval of commercialization. The FDA also requires that, even though it's not explicit in their guidelines. That is certainly a concern that has been extended to any adjunct treatment that appears in the space, obviously triggered by negative experience around SGLT2 inhibitors, but also GLP-1 agonists at times. Clearly, that is something that we need to address ultimately with our safety database. We conducted a small proof of principle study to see whether cadisegliatin has any risk of that. Again, it was a small study. We simply withdrew insulin infusion in patients who were bearing insulin pumps. That's a fairly predictable way of eliciting ketosis and potentially diabetic ketoacidosis, and we did not see an increased risk in that study. Also, when you think about it mechanistically, ketoacidosis evolves because organs don't receive enough glucose and they switch to burning fat, which creates ketone bodies. We are actually helping your liver to maintain the flux of glucose inwards, even though insulin levels may be low. So mechanistically, actually, we are quite confident not to have this potential risk. Yeah. Can you discuss the phase III CATT1 trial design in more detail, which you're now enrolling? You kind of mentioned the timing for completing enrollment in the third quarter, which is coming to a close soon. So, is that on track still? Yeah. I think we are on track. We are going to update the community once it is done. The CATT1 study is a randomized controlled placebo-controlled study. The study is relatively small, but it is a critical study for us to demonstrate that we can reduce the risk of hypoglycemia in a prospective way. Hypoglycemia is the principle endpoint, the primary endpoint. The study is 90% powered to show a reduction of 30%. In that endpoint, the key secondary endpoint is HbA1c, of course, and the minimum expectation is that do not make A1C worse. Because it is easy to reduce your hypoglycemia risk by just reducing insulin dose, but that means that you have more hypoglycemia and high A1C. Clearly, FDA wants to see that we do not disimprove or worsen A1C, 90% power for a non-inferiority, 70% power to show superiority. As I said, it is a three-arm study, so we have two doses of cadisegliatin, once daily and twice daily, and of course, the insulin-only control group. Yeah. What is the phase III power to show in terms of reduction of hypoglycemia events relative to insulin alone, and what would be considered meaningful for the community? Yeah. As I said, 30% is the powering for this study. FDA sort of feels 20% is clinically meaningful in terms of reduction. As I said, in the phase II study, we had a 50% reduction, so we are somewhat optimistic that we can beat that bar. Yeah. How important is hitting on secondary endpoints? You mentioned A1c, which you don't need to show necessarily improvement on, but if you did, what would that mean for the profile, along with other glycemic control endpoints like time in range, et cetera? Yeah. Clearly, now that continuous glucose sensing is very common, and certainly by the time we hope to get approved, it's going to be pretty standard here throughout the world. It's important to assess glucose CGM metrics. Our study uses study CGM sensors in all subjects. So we have the opportunity, over the six-month duration of the study, really, to collect a lot of good data based on CGM. So time in range, time above, below range, the variability of glycemic control is going to be part of the package, if you like. We're also looking at insulin dose. We noticed in our phase II study that many patients were able to reduce their insulin dose, which makes sense because cadisegliatin takes away some of the burden that insulin otherwise would have to shoulder. Yeah. That may have positive implications down the road in regards to insulin resistance or maybe also weight gain, which is an increasing problem even in the type one diabetes community. So these are important endpoints. Then we have patient-reported outcomes. Clearly, we will need to link the numerical reduction in hypoglycemia to clinical benefit. So we have a number of PRO instruments that measure the impact of hypoglycemia on daily living, fear of hypoglycemia, things like that, hypoglycemia unawareness. So all that is going to be part of the data package then, ultimately. Yeah. Given the CATT1 trial is fairly small, you mentioned 150 patients, how are you currently thinking about any additional trials that might be necessary for FDA approval, and what might those look like? Yeah. Our assumption right now, of course, is that we have to do one or two more studies to also meet the exposure requirements in terms of size, but also duration. That's some part of our ongoing discussion with the FDA, how that is exactly going to look like in terms of size and patient population. But that's the given. Once we have the CATT1 data, we're obviously going to pivot to engaging with these larger studies. Yeah. What does the market opportunity look like for treatment prevention of hypoglycemia in type one diabetes, and what do you kind of estimate as the unmet need currently? All right. I could take that one. The analogy we use is imagine driving along the side of a mountain on a really windy road. On the left-hand side, you have the mountain wall, and on the right-hand side, you could go over the side of the cliff. Because of insulin's narrow therapeutic index, this is what people living with type one diabetes deal with every single day. On the one hand, if you scrape the car against the left side, against the mountain wall, that's hyperglycemia. It damages the car, and then over a decade, that's when you get the long-term consequences of diabetes, such as neuropathy, blindness, so on and so forth. On the other hand, you could go over the side of the cliff. That's hypoglycemia. That's much more acute. If you become hypoglycemic, you get confusion, coma, and even death. This is really due to the inherent narrow therapeutic window of insulin, this narrow band that you have to drive in. Today, there's 1.5 million people living with T1D in the United States, 75% of which do not get to the target hemoglobin level of seven or below. That number is 9.5 million globally, and it's growing, estimated to get to 40 million by the 2030s. There's been nothing new on the adjunctive side, no known oral adjunctive treatment to insulin in over a century. When you think about the market opportunity, and again, it's a little bit early, we're not going to give true numbers, but you can think about massive unmet medical need. If there were to be a safe, effective, convenient treatment option, it would be the only additional thing to insulin. I mean, today, you have fast-acting insulin, short-acting insulin in a pump, a pen, inhaled, but it is all still insulin with that narrow therapeutic index that I referred to that causes you to have to sort of be driving down that windy road. You can envision if this drug were to get approved, there would be really nothing to step at it against because there is nothing else. Again, there is just insulin. If people wanted proof of episodes of hypoglycemia, today, with the prevalent use of continuous glucose monitoring systems, you can literally hit a button and download, "Hey, I had X number of hypoglycemic events over the last month." Again, I think we feel very, very good about the commercial opportunity for this cadisegliatin. Okay. You announced last week that you will be hosting a KOL call later this year on CADI and type one diabetes. What are the key topics that that will consist of, and any additional or new data that will be highlighted? Yeah. We will be hosting a KOL event on October 20th. You can go to our website and register if you are interested. We will have two KOLs, two physicians that are actually in our ongoing trial that are also very familiar with cadisegliatin. They participated in some of the earlier studies, so I think that they have firsthand experience with the drug, and more importantly, really discussing the unmet medical needs. Again, when we say hypoglycemia, if you have type one diabetes, you fall into one of two camps. If you treat aggressively to try to get your hemoglobin A1c below seven, you are more likely to have recurrent hypoglycemic events. Alternatively, a lot of people just do not want to even go there. So they sort of decide, "You know what? I am going to let my hemoglobin A1c suffer because that is a longer-term issue, and I will let my blood sugars ride high." So, again, it is almost two sides of the same coin. It is either you are getting hypoglycemia or fear of hypoglycemia. So we want to elucidate some of that. We do have some new market research that we performed internally that will be disclosed for the first time, and there will also be a world-famous musician who will be our sort of patient person who is going to speak to what it is like to live with type one diabetes on a daily basis. Perfect. You also recently announced plans to initiate a Phase II-A hybrid CATT1 trial, which looks at hybrid closed loop systems. What is the timing guidance for this trial, and what are you hoping to show here relative to the original CATT1 trial? Yeah. The CATT1 study excluded hybrid closed loop users, simply because that's what FDA wanted us to do. This is our foray into the hybrid closed loop world, which is going to increase in, currently, about 40% of patients in the U.S. use closed loop. It's about 30% in Europe. But we're expecting this number to certainly rise significantly by the time we get to NDA or MAA submission. So, the study is to examine what are the impact on glycemic control in the somewhat more short-term framework. We hope to start recruiting in the third quarter and also probably in a similar timeframe, report results as CATT1 next year. Mm-hmm. Are you eventually looking to transition into hybrid closed-loop systems for Phase III, or would this be a separate population that you evaluate? It is certainly a separate population because the technology has a significant impact on how people handle or manage their diabetes. So it's always worthwhile studying them separately somewhat from, let's say, pen users or people who use open-loop pumps. In future studies, certainly they're going to be included. This study is going to help us also better understand the operational challenges. There's more technology involved, so integrating this into the data collection is going to be critical for us. That's another big objective for this pilot trial, so that we are well prepared next year to start a dedicated Phase III study in that population. Okay. Can you remind us of your cash position currently and ability to fund these CATT1 trials? Yeah. So last reported cash was approximately $87 million at the end of the second quarter, and what we've publicly said is that's plenty of cash to get us through the CATT1 top-line data with runways. So absolutely financed through that catalyst. For additional CATTs, look, it's really all about CATT1. That is the main focus of the company. From the time that you see the press release announcing completion of enrollment, the way to think about it is the study's another six months, and then add a couple of months for us to clean up the data, then present it for disclosure. So you'll be able to do the math when you see that press release. I think the only other catalyst that is worth mentioning is the hybrid CATT study, hybrid closed-loop study, should read out after the top-line data from the CATT1 study. Perfect. Great. Thank you so much, Michael and Thomas. Thank you. Thanks everyone who has been listening in. Hope everyone has a great rest of their day. Thanks. Thank you.