Good afternoon, everyone, and welcome to the vTv Therapeutics Virtual KOL Event. At this time, all attendees are in a listen-only mode, and a question- and- answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the vTv website following the conclusion of the event. I'd now like to turn the call over to Paul Sekhri, Chairman, President, and CEO at vTv Therapeutics. Please go ahead, Paul.
Good afternoon, everyone, and welcome. I'm Paul Sekhri, Chairman, President, and CEO of vTv Therapeutics, and on behalf of the entire team, thank you for joining us today for our KOL event on hypoglycemia in type 1 diabetes and the cadisegliatin phase III program. Next slide, please. Before we begin, I'd like to remind you that today's presentation and accompanying remarks may include forward-looking statements about vTv's plans, products, operations, and other matters as reflected in this slide. Also, today's guest speakers are independent clinicians and advocates who have generously agreed to share their time and expertise. The views they express are their own opinions and do not necessarily reflect the views of vTv Therapeutics. Next slide, please. Today's agenda focuses on the burden of hypoglycemia in type 1 diabetes.
Despite advances in diabetes management technology, hypoglycemia remains a persistent burden, one that extends beyond individual episodes to daily vigilance and fear of going low. We'll bring together clinical expertise, lived experience, and market research to better understand that burden. We'll begin with the clinical picture of hypoglycemia and then hear directly from someone living with type 1 diabetes. That perspective will bring that clinical picture to life. Next, we'll share findings from our recently completed market research, building on the clinical and personal perspectives you'll hear today. We'll then turn to cadisegliatin, our lead investigational program in its phase III CATT1 clinical trial, followed by a brief corporate summary. We'll then conclude with a question- and- answer session. Now let me introduce our guest speakers on the next slide.
Our first featured speaker today is Dr. Schafer Boeder, a board-certified endocrinologist, medical director at Paradigm Clinical Research, and associate professor of medicine at the University of California, San Diego. He'll explain why hypoglycemia remains an inherent challenge of insulin therapy, even with today's most advanced technologies. He'll also discuss how its burden extends beyond severe events to frequent lows, impaired awareness, and fear of hypoglycemia, shaping daily life and decisions about glucose management. I'll then be joined by internationally acclaimed cellist Alisa Weilerstein. Alisa has lived with type 1 diabetes since age 9. She will take us inside a day in the life of someone living with type 1 diabetes. We'll talk about quality of life, the anxiety and fear that come with the risk of a low, and where today's technology still falls short.
Our third guest speaker is Dr. Klara Klein, Assistant Professor in the Division of Endocrinology and Metabolism at the University of North Carolina at Chapel Hill and Director of the Endocrinology, Diabetes, and Obesity Clinical Research Unit. Dr. Klein will review the expected mechanism of action of cadisegliatin, review the phase II data, and walk through the design of our phase III CATT1 clinical trial. You will also hear from Martin Lafontaine, vTv's Chief Commercial Officer, who also lives with type 1 diabetes, and he will present findings from our recently completed market research. With that, I will turn it over to Dr. Schafer Boeder to discuss hypoglycemia in type 1 diabetes.
Thank you, Paul. It is a pleasure to be here today. I am looking forward to this discussion, and my goals today are pretty straightforward. I want to spend some time introducing type 1 diabetes, talking a bit about how we approach therapies for type 1, and then ultimately pointing out why despite our current therapies and advances in technologies that we use for type 1, hypoglycemia remains a major problem. These are my disclosures. I will begin with type 1 diabetes. Type 1 diabetes is characterized by autoimmune attack on the beta cells of the pancreas. These are the cells that actually produce insulin, and this is a process that has nothing to do with diet or lifestyle, but clinically diagnose it.
We see antibodies sometimes happening years or decades before there is any sort of clinical evidence of disease. Over time, this autoimmune attack kills off the beta cells and will ultimately lead to absolute or near absolute insulin deficiency. By the time type 1 diabetes is diagnosed in an individual, that individual usually needs insulin, usually needed it yesterday, and will therefore need insulin for a lifelong, from thereafter, not just to maintain blood glucose control, but actually to survive. This is a disease that affects roughly 2.1 million individuals in America. Global estimates are close to 9.5 million.
Interestingly, this is a disease that we have traditionally thought of as sort of a childhood disease or a pediatric disease. It is not. It certainly is an important disease in children, but the vast majority of people living with type 1 diabetes are adults, and you can be diagnosed at any age. Importantly, too, these numbers are increasing. We have seen not just in the U.S., but globally, that the number of people living with type 1 diabetes is increasing rapidly.
The standard of care now for the treatment of type 1 diabetes, of course, we use insulin, but how do we deliver it? Diabetes technologies are really the cornerstone of our therapies for people living with type 1 diabetes. These include continuous glucose monitors. These are sensors that are worn on the skin with a small filament that goes under the skin and continuously senses the blood glucose values and reports those out. We also use insulin pumps.
These are external devices with small cannula that sit under the skin and deliver that insulin, both continuously providing sort of an ongoing insulin amount that's circulating in the body, but also used for boluses or for more insulin amounts that go along with meals or to correct for high blood sugars. More recently, our standard of care has become automated insulin delivery, and this is when we have a CGM combined with an insulin pump and an algorithm to tie that all together so that the insulin pump is able to automatically adjust the amount of insulin that's being given in response to the blood glucose being measured by the CGM. We know these technologies are useful. They certainly improve our diabetes care.
When we look at CGM alone in comparison against the old traditional finger stick glucose values, they improve A1C values by about a quarter of a percent. This is a clinically meaningful amount. They increase time in range, and I'll talk a little bit about our time in range targets, but time in range that we want people to have blood glucoses that are generally between 70 and 180. That's our target range, and the higher the time in range, the more time that's spent in that range. So an increase in time in range of about 5.6% by CGM, that's equivalent to about 80 minutes per day spent in target range. CGM can also reduce hypoglycemia, so the amount of time spent below range, that's with a blood glucose less than 70 by 2.4%.
That in and of itself is a reduction in time below range of about 30 minutes per day. So these are really important numbers. However, even amongst individuals who are using the most advanced AID system, these second generation AID systems that are currently commercially available, 42% of them reported that their A1C was not at target. So these systems are good, but they have not completely solved our problems. Here we see some of our target ranges that we use in our CGM metrics. Our target range is there in the middle in blue, right between a blood glucose of 70 and 180. That's where we want our folks living with type 1 diabetes to spend most of their time. Above that, we consider hyperglycemia. That's time above range, a blood glucose of 180 or higher.
Hypoglycemia, we begin to define as a blood glucose at 70 or less. So below 70 is hypoglycemia. Above 180 is hyperglycemia. We know hyperglycemia, high blood glucose over time can increase the risk for chronic complications, so damage to eyes, kidney, nerves, as well as the heart and other vital organs. So over time, we know that it's really important to minimize time in hyperglycemia. However, when we use insulin to do that, we unfortunately increase the risk of hypoglycemia, low blood glucose. Hypoglycemia can be acutely dangerous, causing things like seizure, loss of consciousness, increased risk for falls and accidents. As providers and certainly people who are actually living with the disease day to day, we are constantly fighting against these two opposing forces.
We know from good data and good studies that decreasing hyperglycemia is important for reductions in long-term complications. However, more intensive insulin therapy directly increases the risk of hypoglycemia, and in particular, severe hypoglycemic events. Why is this happening? it is really just the nature of external insulin therapy. When we give insulin through the wrong route, normally insulin is secreted from the pancreas. When we give insulin through an injection under the skin, it acts very differently.
Normally, insulin is secreted from the pancreas in an individual who does not have T1D, gets secreted into the portal circulation. It enters the liver, where it has its first effect. In fact, 50%-70% of the insulin that is released from the pancreas actually is used or pulled out by the liver, and the rest of it gets circulated into the rest of the body. That process is relatively quick.
Pancreatic insulin released from the pancreas in a normal functioning system peaks its activity at around 15-30 minutes, and then by about two hours, that insulin is completely out of the body and no longer functioning. When we give insulin under the skin, it sits there, it is slowly absorbed, and the peak of that insulin action is about two hours after the initial bolus or the initial injection. Then the tail of that insulin action continues for many more hours, oftentimes four or five hours, or in some cases longer. Especially in that tail, when that insulin is continuing to work, that is a really high-risk period for hypoglycemia. it is the wrong route, it is the wrong timing, and there is no recall of this insulin. Once it is injected under the skin, there is no taking it.
Using glucagon or carbohydrates to raise the blood sugar, but to really get rid of the insulin, there is nothing we can do. We just have to wait for that insulin effect to pass. Really importantly, T1D also impairs the body's natural defenses against hypoglycemia or falling glucose. In someone who does not have diabetes, as the blood glucose were to fall, let us say after a meal, as it came back towards normal, once it hits a blood glucose level of around 80, the pancreas stops secreting insulin. There is no more insulin being secreted and entering the system.
If the blood glucose were to drop further, there are certain counterregulatory hormones that are released. Glucagon is released from the pancreas, norepinephrine and epinephrine are released, and together, these hormones help fight against falling blood glucose and actually start to raise the blood glucose back up. If the blood glucose gets low enough, around 50 mg-55 mg per deciliter in most people, then both autonomic and neurologic warning system begins to go off. We feel symptoms of shaking, sweating, we get very hungry, and it elicits a behavioral response. That person, before they get lower and their blood sugar gets more severe, they are able to eat something and treat themselves. it is a really important warning system.
Unfortunately, all of this is different in T1D. Of course, the pancreas is not secreting insulin. We cannot turn off the insulin once it is delivered. The glucagon response is generally lost or at least severely impaired in people with T1D, as well as the other counterregulatory hormones, so that the body's own defenses against hypoglycemia are no longer functioning appropriately. Ultimately, especially with recent or recurrent hyperglycemia, that neurologic response is also absent, and that's what we call impaired hypoglycemia awareness. So that early warning system that, hey, you're low and probably going lower is completely gone. That's how people who have recurrent hypoglycemia can oftentimes find themselves in recurrent severe problems.
We know that technology certainly can help with this, but unfortunately, it has not solved this problem. Data from the T1D Exchange show that individuals, adults with type 1 diabetes who are not using CGM, the continuous glucose monitors, report a severe hypoglycemic event, at least one severe hypoglycemic event 34% of the time in the last year. In individuals who are using CGM, that number drops, so only 18% of those individuals report a severe event, at least one severe event in the last year.
That's still, of course, close to one in five people. Even in those using the most advanced AID systems, those numbers are not significantly improved, with one in six of those individuals having a severe hypoglycemia event, at least one in the last year. This is really, honestly, an unacceptably high rate of severe events. When we look at data using this a claims database that includes almost 68,000 U.S. individuals, adults with type 1 diabetes, we see that over a decade, despite improvements in insulin and insulin delivery technologies and CGM, we didn't really make a dent on the rates of severe hypoglycemia. So, we have a lot of work to do in this space. Importantly, hypoglycemia is a spectrum.
We talk a lot about severe hypoglycemia, and rightfully so, because those are acute and severe and very dangerous events. They're also probably the easiest to measure because severe hypoglycemia is defined as requiring assistance from another person to recover from the hypoglycemia event. Oftentimes, a severe event or a level 3 event will land that individual in the ER or even being admitted to the hospital. So we can measure these. They are scary and they're severe, but it's really just the tip of the iceberg. Level 2 hypoglycemia events are defined as blood sugars less than 54. These are considered clinically important hypoglycemia. Level 1 events are blood sugars less than 70.
These are very common in people living with type 1 diabetes, but we should consider this an alert threshold and an opportunity for someone to make an intervention, to understand that they're low and may potentially going lower, and hopefully prevent that from getting worse. It's still a really important number, and it's very common. It interrupts that individual's day. It requires some type of intervention, some type of action. Underlying all of these types of hypoglycemia, all these different severities are the impaired awareness of hypoglycemia, and fear-driven behavior that's a response to those hypoglycemic events. These, unfortunately, are burdens that follow people who are living with type 1 diabetes every single day.
The data from the next few slides come from an online survey of 674 U.S. adults with type 1 diabetes. This was a study that was sponsored by vTv but was actually completed by dQ&A back in 2025. It really helps us define these four clinically meaningful hypoglycemia burdens experienced by people living with type 1 diabetes and experiencing hypoglycemia. These outcomes, importantly, were presented earlier this year at the International Hypoglycaemia Study Group meeting.
Also, just by way of background, the people who responded to this survey were a very high technology use group. These were individuals with T1D. Almost two-thirds of them were using AID systems, and almost all of them were using CGM. So these are individuals who are very engaged, and these were their responses. I think that's important just when we all kind of look at the numbers. Everything here is self-reported, and if there's published data that exists, I've added that alongside for comparison. The first hypoglycemia burden is frequent level 2s, and for the case of this survey, this was defined quite narrowly as having a blood glucose less than 54, that's a level 2 hypoglycemia, but occurring daily, almost daily, or a few times per week. So this is really frequent level 2 hypoglycemia events.
In this high technology group, a quarter of these individuals reported having this. So this is obviously still very common, even amongst AID users. Another 15% reported a severe hypoglycemia event, a level 3 hypoglycemia event within the last year. This is important because if you've had a severe event, that's actually the strongest predictor for a subsequent severe or level 3 hypoglycemia event. 18% of these individuals reported impaired awareness of hypoglycemia, where they rarely or never feel the warning symptoms of a low. Again, this is dangerous for obvious reasons, if they're going low and they don't know it. This also, of course, raises risk for future events. Finally, amongst these individuals, for those whose A1C was not a goal, strongly agreed that they keep glucose high or can't aim lower because of hypoglycemia.
In this case, almost half of these individuals who were not a goal set said that the fear of hypoglycemia was a strong barrier to them achieving glycemic targets. This is really common to prior data that we've seen in this space. I would say, in other reports looking at rates of severe hypoglycemia and level 2 hypoglycemia, as well as impaired awareness of hypoglycemia, actually show higher rates of this occurring. I think that because this is a pretty engaged group that probably responded to this survey, it may, if anything, underestimate the rates of these burdens across the population of T1D.
If we zoom in and look at this data in another way, when we try to count each individual who has at least one clinically meaningful burden of hypoglycemia, I'll walk you through the way that this is presented. Beginning on the left, individuals reported if they had frequent level 2 hypoglycemia. If their answer was yes, they were counted in the first column. If their answer was no, then we looked to see if they'd had any prior severe hypoglycemia in the last year. If they had at least one severe event in the last year but had said no to the frequent level 2s, they were counted in the second column.
An additional 10% who said no to the first two columns reported positive symptoms of hypoglycemia unawareness, so impaired hypoglycemia awareness. Then if all of those were no, amongst those individuals who A1C was above 7, who reported that the fear of hypoglycemia was a barrier to improved glycemic control, was put in that fourth column, and that was at 20%. When we add these all up, counting each individual just once, many individuals will fall into multiple categories, but counting them just one time, we see that 65% of these individuals have at least one clinically meaningful burden.
I would say it's important to point out with this data that it was weighted for A1C to help the survey responses better reflect the true type 1 diabetes population. This was amongst all respondents of the survey. When we look at the same data, but zooming in specifically on those individuals, which is about two-thirds of this group who were on AID, these are the numbers that we see. 22% reported frequent Level 2 hypoglycemia. An additional 8% who didn't have that reported a recent severe event in the last year. An additional 10% had impaired awareness of hypoglycemia.
An additional 14% reported that hypoglycemia was a barrier to improved control. Over half of these individuals on the best therapy that we have for type 1 diabetes are still dealing with at least one clinically meaningful burden. Hypoglycemia, I think, just importantly, and this will be something that Alisa Weilerstein and others will be able to potentially speak to, this is something that really affects people living with type 1 diabetes day in and day out. This is not an event that comes and goes, and then we can forget about it. Hypoglycemia affects sleep. Sometimes hypoglycemia occurs at nighttime and is completely missed. That's actually quite dangerous. If it's not missed, then it leads to being awake and treating that hypoglycemia, so it leads to daytime tiredness.
It can affect the sleep of not just the person living with type 1, but other family members and those who are nearby. Any time that someone's driving or doing some type of potentially dangerous event, they need to be aware of their blood sugar, so they need to be checking their blood sugars and potentially intervening on those things. Hypoglycemia at work can be a major problem. Not only does it slow down your cognitive thinking and the quality of your work, but it can interrupt a meeting. It can be disastrous when it happens during a test, and I have colleagues and friends who have had these experiences. Exercise is an issue with hypoglycemia.
Exercise increases the risk of hypoglycemia, but of course, it's really important for one's health, so it requires a lot of planning, understanding how much insulin's on board, how many carbohydrates need to be taken, et cetera. It can have a major effect on social life and other outside activities. Things like travel, dining out, drinking alcohol, enjoying time with friends can all be affected. Hypoglycemia requires constant vigilance, always being prepared to treat it and deal with it when it does happen, because it will happen, and a shared burden, not just with the person who's living with the type 1 diabetes who's dealing with it all of the time, but also those who are around them, loved ones and caregivers as well.
Fear of hypoglycemia is really important, and it's actually a learned but completely rational response to experiencing hypoglycemia. If someone's had a frightening low blood sugar, whether it be something that was mild and uncomfortable or something that was severe and life-threatening, it may have happened in public, it may have happened while driving. These things appropriately elicit fear in individuals who have T1D. That leads to fear of the next one, and then a sort of an adaptive protective response, a behavioral response by that person living with T1D. They may let their blood sugars run higher. They may skip some insulin doses or reduce their insulin doses. They may have to snack more or eat more food to raise their blood sugar.
All of these things actually can be somewhat effective, ultimately, in terms of reducing the frequency or severity of hypoglycemia. In turn, it's raising the A1C, it's raising the average blood sugar and putting them at risk for increased long-term complications. This is an unfortunate cycle, and we know that 43% of individuals from the T1D Exchange reported fear of hypoglycemia was a barrier to achieving optimal glycemic control. This fear of hypoglycemia and the related behaviors to that account for roughly about a half of a percent of increase in A1C. That's a significant number that we really wish we could improve upon. There's a famous saying in diabetes that hypoglycemia begets hypoglycemia, and that's because recurrent hypoglycemia, especially Level 2 hypoglycemia or severe hypoglycemia, Level 3, further blunts the body's own physiologic response to low blood sugar.
The adrenaline symptoms become less strong, the ability to impaired hypoglycemia awareness, and ultimately, people with impaired hypoglycemia awareness have 6 times more severe events than those who do not have that. This is a really scary and unfortunate cycle of people living with T1D that they can get into of low blood sugars, and then having impaired awareness, then having more low blood sugars. Acutely, low blood sugars can be super dangerous. They can impair thinking, they can cause injuries, they can cause car crashes, they can cause seizures and comas, they can lead to falls, and they can cause cardiac arrhythmias. We know in the long term, recurrent hypoglycemia is also associated with poor outcomes, with poor cardiovascular outcomes.
There's potential effects to cognition over time, and these account for an estimated 8% or more of deaths in people with T1D who are under 56. It really is a problem both in the acute setting and in the chronic recurrent setting. To summarize, hypoglycemia is unfortunately intrinsic to the way that we treat T1D by giving insulin through the subcutaneous tissue. Once we give that insulin, we can't switch it off. The burden related to hypoglycemia is extremely broad, and it's not just severe Level 3 hypoglycemia events, which are extremely scary and extremely dangerous, but it's also frequent Level 2 hypoglycemia, impaired awareness of hypoglycemia, and fear driven avoidance. Technology has been a huge boon to treating T1D, and it does help somewhat with hypoglycemia.
Yet, even in our most advanced systems, over 54% are reporting regular burdens of hypoglycemia and are experiencing true hypoglycemia. Technology has been a boon, but has not been a panacea by any means. Recurrent hypoglycemia shapes behavior and ultimately glycemic control and affects our outcomes, not just in terms of the hypoglycemia, but in terms of long-term complications and things that we really want to avoid. I really appreciate vTv working on this problem. I will pass this back to Paul.
Thank you so much, Dr. Boeder. We now turn to Alisa Weilerstein, my dear friend and world renowned cellist. Thank you so much for joining us, Alisa.
My pleasure. Thank you for having me.
Before we just talk about your experience of living with T1D, could you just briefly introduce yourself?
Yes. My name is Alisa Weilerstein. I have been living with Type 1 diabetes since 1992, so that is 34 years. I have been playing cello professionally around the world since I was 13 years old. I started playing when I was four, but professionally since I was 13, and I am the mother of two young daughters, ages 10 and four.
Awesome.
You mentioned that you were diagnosed with T1D just before your 10th birthday, and have now lived with it for more than 30 years. For someone who does not live with T1D, what does managing the condition require of you, both personally and of course, professionally?
The toughest thing for me about, and I am sure I share this with many, is it is a 24 hours a day, seven day a week, 365 day a year job that has never taken a day off or an hour or a second off in its life. It is always there, so it is constant vigilance really. I was listening intently to the last presentation, which is sadly very accurate. It is always a balance, and especially since we do have the technological tools to help us stay in tight control, they are extremely imperfect still, unfortunately. We are constantly trying to keep everything in balance with life as we try to live our lives as well.
How would you describe hypoglycemia affecting your daily life, kind of both personally and professionally as well?
Sure. I especially appreciated in the last presentation talking about the fear of it, because that's always there. Especially in a life that is very unpredictable like mine, because travel is such a huge part of my job description. Being on stage, which there's plenty of adrenaline and hormonal fluctuations, which of course affect blood sugar. It's a huge part of my life and of course, just the daily life of being a mom of two school age kids. It's very active. Of course, they're up early, they have a thousand activities to get to, and there's so much planning around them, and you have to be very present and driving and spontaneous things, kid gets sick, that kind of thing. You have to just be on, and so working parents have to be.
I do always, of course, have to carry plenty of blood sugar raising glucose tablets, that sort of thing with me. I'm also constantly, of course, count I don't know what it's like to look at a plate of food and not count what's on there. I literally don't know how to do that anymore, to not count my food. Of course, planning for exercise, planning for how adrenaline will affect my blood sugar going on stage. The other thing which I think we don't focus on enough is that even though we have these amazing algorithms that are now attached to us, we are not algorithms, therefore, blood sugar is not predictable, by definition.
Even though I do have plenty of experience being on stage and with all of the things I just mentioned, the blood sugar may just decide to do something else, and therefore I constantly have to be prepared. Hypoglycemia, if I were to get low on stage, it would literally be disastrous. I play the cello, it requires a tremendous amount of manual dexterity and very fine motor skill, and of course, that's the first thing that hypoglycemia destroys, and so basically my fingers just would not work. I would also get very confused and shaky and I tend to also wear high heels on stage and could fall, those sort of things as you know.
Of course, to say nothing of daily tasks like driving or cooking for my family, or even being in an airport, being in a security line and there's really nothing you can do. Then if you get low in the middle of all of that, it's quite disastrous maybe for your person as well as the people around you. So it's always there. That's the thing. It's always there.
Yeah. You mentioned that you use an AID, automated insulin delivery system.
Correct.
How has that technology improved your life, and in what sense has it had an impact on hypoglycemia for you?
It certainly improved my life. I want to give credit where credit is due. I think that my two pregnancies are a good example. My first pregnancy was in 2015, 2016, so I had a continuous glucose monitor, but I had a dumb pump. Even though the continuous glucose monitor was already a vast improvement upon finger stick testing, which as we know, they're just snapshots in time and can't show a trend of blood sugar, it still required plenty of mental gymnastics to make the pump agree with it. My second pregnancy was in 2021, and therefore I had the closed loop system and the Control-IQ technology. The pump was more responsive to the blood sugar. However, plenty of things still go wrong with this technology. Sometimes it doesn't work, sometimes the sensor is not accurate.
Very often, I think, actually, and I think we don't emphasize this enough, that sensors are about 20 minutes behind what blood plasma is. Therefore, they sometimes just don't catch those. I might actually feel like I'm low, but my sensor might say that I'm at 95, and I could just have been dropping too fast for the sensor to catch it. Therefore it might make me doubt and then delay treatment, and that, of course, is terrible. But overall, of course, the system has certainly helped.
Oh.
Knowledge is power with diabetes, and it certainly gives me a lot more information than I had before.
Awesome. Finally, obviously short of a cure, what would an ideal outcome look like for you as someone living with type 1 diabetes?
Well, something that would take the mental burden of living with this away would be, short of a cure, of course. It's almost too wonderful to allow myself to think about. I think this is something that you and I have touched upon before, that when I was diagnosed, and to their credit, my doctors impressed upon me the message that, if you take care of yourself, you're really vigilant, you can live the life that you want. So that is to a very large extent true. I am living the life that I want with a lot of determination and a lot of mental gymnastics, or mental load, as we like to say now, which is attached to living with type 1 diabetes.
The mental load, it's almost difficult for me to even talk about because it's difficult to describe because it is present in every decision that I make. Even joining this wonderful event that you're having, the amount of planning that goes into that, planning the food and how the blood sugar's going to trend, and my exercise session when I was practicing the cello. Every step leading up until this, I'm planning and trying to avoid going too low or having a hyperglycemic event. So something that is going to lessen that burden and that would make blood sugar more stable as a complement to insulin therapy would be such a game changer.
Awesome. Alisa, thank you so much for sharing your story, your perspective.
Of course.
Especially given your absolutely crazy schedule. So appreciate it so very much. Next, Martin Lafontaine will share how these experiences show up in the market research that we've been doing lately. Martin.
Thanks, Paul, and very enlightening to hear Alisa's talk. Thank you, Alisa. It's nice to be with you all this afternoon, and the first thing I'll do is to put some perspective on our program and to complement some of the points that have been raised by Dr. Boeder and Alisa previously. We at vTv often use the metaphor that living with T1D is like driving a fast car on a very narrow, slippery, and dangerous mountain road as the one you're seeing on this slide right now.
And what we mean by that is that every time you deliver insulin several times per day, you're constantly veering between either scraping the car on the rock wall, damaging the car bit by bit, which analogues to hyperglycemia, which increase the risk of long-term complication, as we heard earlier, or alternatively, if you choose to manage your blood sugar very tightly, closer to normal levels, as you should, by driving along the cliff, and you do so in order to reduce the risk of complications, but then you increase the risk of having acute hypoglycemia. You can even crash the car, as these events, as you heard, can go anywhere from being life disruptive to potentially being life threatening. But no events, whether they're mild, moderate, or severe is fun.
So in our metaphor, this narrow road simply reflects insulin's narrow therapeutic window that people with T1D must maneuver every day, or I should say, at every insulin injection. Some may tolerate an increased risk or frequency of low blood sugar to keep their blood glucose closer to normal, while others may err on the side of caution and intentionally drive that car closer to rock wall, but then trading off long-term health consequences for short-term safety. So it's always about that trade-off. So we believe at vTv that new interventions that can address this core fundamental limitation of insulin are needed by helping to establish, on this slide, a safety guardrail along that cliff to protect people against low blood sugar, and this is what we're working on at vTv. Next slide.
So when it comes to the commercial opportunity, our belief is that if approved, cadisegliatin may represent a large opportunity for several reasons. First, because it targets a large population with about 2 million Americans living with type 1 diabetes and growing, meaning that every 10% penetration rate of that population translating to about 200,000 patients on therapy, which is quite significant. Two, it targets an important unmet medical need in the fact that 75% of people with T1D do not achieve that A1C target of less than 7, which expose them to a greater risk of long-term complications. So we're doing better, but we're not doing well as of yet. And hypoglycemia is playing a major role, not to say a critical role.
It is cited in the 2026 ADA and EASD joint consensus statement for the treatment of T1D adult as being not one, but the most important limiting factor in the glycemic management of people with type 1 diabetes. And again, hypoglycemia is not rare, something which is very common. Most people living with T1D are having several mild to moderate events in a typical week. And despite this population, this unmet medical need, there hasn't been any oral adjunct therapies to insulin, and only one injectable, in fact, approved by the FDA since insulin was discovered more than 100 years ago back in 1921. So what we mainly have today are different insulins that act faster, slower, or act longer, and different ways to administer it.
With about 60% of the 2 million Americans living with T1D, or about 1.2 million people, using multiple daily injection plus a CGM or finger stick blood glucose monitor to monitor their blood glucose, while about 40%, as of today, make use of an insulin pump or an AID system if they also have a CGM. This is quite a contrast compared with the different options from a therapeutic standpoint, which are available for people living with type 2 diabetes. For all these reasons, we believe that cadisegliatin represents a major opportunity to address a critical gap in what has been a, can't say long, but I'll say very long overlooked market, the T1D therapeutic market. That's the scale, call it, of the problem.
Now let's hear more about the burden of hypoglycemia in the words of people living with T1D themselves to complement what we heard from Alisa Weilerstein. Here are some results of a survey conducted by vTv with more than 700 U.S. adults living with T1D, in which around 95% were technology users, meaning they were using either a CGM or an AID system. In this survey, what we've seen, for one, is that 88% of participants either strongly or somewhat agreed with a simple visceral statement, "I hate having low blood glucose," which speaks to the type of relationship that people with T1D have with hypoglycemia. And remember, the majority have several such episodes in a typical week.
Two, in T1D individuals with an HbA1c above 7, close to 9 out of 10 either strongly or somewhat agreed to often keeping their blood glucose higher than they should to avoid lows, or that they would aim for lower blood glucose if it was not for the risk of hypoglycemia. Again, speaking to the broader role that the risk of hypoglycemia plays on overall glycemic control, i.e., driving the car on the left side of the road, if I go back to my driving analogy, which again damages the car bit by bit. In the third box, we see that this attitude and behavior towards hypoglycemia is no different amongst those with an HbA1c above 7, despite making use of an AID system, the current most sophisticated technology.
Then the next question becomes whether the people prescribing their treatment or therapies do see hypoglycemia in the same way. Next slide. In an online survey that was conducted by vTv with both EU and U.S. endocrinologists, 85% of U.S. adult endos, the vast majority, stated that the short-term risk of hypoglycemia is either an equal or a higher treatment priority than the long-term risk of hyperglycemia for most of their T1D patients. Hypoglycemia appears to be a priority 78% strongly agree or agree that avoiding hypoglycemia is a significant clinical challenge in managing their T1D patients. Hypoglycemia is a priority and appears to be a challenging one for adult endocrinologists.
Lastly, a majority of the U.S. endos strongly agree or agree that not only hypoglycemia, but the fear of hypoglycemia that Dr. Boeder spoke about extensively, significantly interferes with the ability for patients to reach that HbA1c of less than 7%. According to the data that we just presented, both on the patient and on the doctor's side, it appears that hypoglycemia is more than just a number, more than just the frequency or the severity of some events, but that the sole risk or idea of hypoglycemia gets in the way to achieve a desired outcome. Hence why, yet again, the ADA and the EASD joint consensus statement for the treatment of adult with T1D states hypoglycemia as being the most important limiting factor in the management of T1D.
That raised the obvious question on how big, therefore, is an addressable population for a therapeutic agent that would aim at reducing the risk of hypoglycemia for people living with type 1 diabetes. Next slide. Our belief at vTv is that the TAM for such agent is virtually all people living with type 1 diabetes, independent of technology use. Our rationale here is quite simple. As Dr. Boeder explained earlier, hypoglycemia is an inherent risk to disease management as exogenous insulin is not subject to the body's normal feedback mechanisms, seeing people who don't have T1D. Again, this is catalyzed by its very narrow therapeutic window.
This is also well supported by real-world prevalence data, which shows that hypoglycemia exposure in T1D is near universal, not occasional, with most people, I said earlier, having several mild to moderate events in a typical week. Remember, as we saw in the survey, they hate those events. If virtually the whole population carries the risk, according to what we just discussed here, the natural next question is to find or define a population carrying, call it the heaviest burden. Next slide.
For such, I'd like to simply refer to the data presented by Dr. Boeder earlier, who spoke about those four groups of people living with T1D carrying highly clinically relevant hypoglycemia burdens, direct and indirect, defined as those who have a lot of frequent level 2 events, those who have a history of severe level 3 event, those who don't feel their symptoms, those with hypoglycemia unawareness, as well as those with strong fear of hypoglycemia behaviors and attitudes linked to suboptimal glycemic control, i.e., an HbA1c above 7.
This is a population that, as we saw, when you stack them up and weigh them for A1C, sums to about 65% of people living with T1D adults, according to the data presented or more. We say or more because I think Dr. Boeder referred to it a bit, is that the analysis presented counted only those who self-reported either daily, almost daily, or a few level 2 events in a typical week, which may be seen as a lot, and also only included those who strongly agree to having hypo avoidance behaviors and attitudes associated with an A1C of 7 or more, versus those who strongly or somewhat agree. If you relax these criteria, it would likely bump up that 65% figure. Next slide.
But as Dr. Boeder also spoke about, this picture, as of now, still holds up even when looking solely at those making use of the most advanced technology, a one clinically meaningful hypoglycemia-related burden according to this framework. Finally, to complement this quantitative analysis that is helping us to quantify a high burden population when it comes to hypoglycemia, we did ask 45 U.S. endocrinologists about their willingness to recommend to these four groups individually, using a four-point scale of definitely, likely, unlikely, or definitely not, a hypothetical once-daily oral adjunct therapy to insulin that would deliver a 30% reduction in the combined rate of level 2, level 3 hypo events without negatively impacting HbA1c, along with a 5% reduction in the total daily insulin dose consumption.
And those 45 U.S. endocrinologists which were presented that description were also told to assume that the therapy was generally well-tolerated with no additional risk of weight gain, nausea, DKA, or high cholesterol compared to only using insulin, and that therapy would also be covered by insurers. So of course, this data is directional, but what we can see is that the willingness to recommend such product concept appears extremely high and consistent across all four burdened populations, ranging anywhere between 84%-96% of adult U.S. endos in this survey, stating that they would definitely or likely recommend such therapy to these individuals, which, as we saw earlier, represent an estimated 65% of the U.S. T1D adult population.
So in summary, the important size of the T1D population, consisting of 2 million Americans and growing, the breadth and the depth of the hypoglycemia clinical unmet need in this population and dependent on the use of technology or not, the lack of options to help solve the unmet need, along with physician willingness to recommend an adjunct therapy to insulin that aims at reducing the risk of hypoglycemia. All of this gives us great confidence in the commercial opportunity ahead for cadisegliatin, if ever approved by regulatory authorities, of course. So on this, I will now turn it on to Dr. Klein, who will walk us through the next part of this presentation. Thank you.
Good afternoon, everyone. I'm Klara Klein, and I'm really grateful that I have the opportunity to tell you about. Let's see if I can advance these slides. I'm grateful for the opportunity to tell you about cadisegliatin as an adjunctive therapy to insulin in people living with type 1 diabetes. These are my disclosures. My overall goal today is really to give you an overview of cadisegliatin's mechanism of action, review the completed phase II data for cadisegliatin, and then outline the ongoing and upcoming cadisegliatin trials.
I'll just take a moment here to note that, throughout the talk, I may refer to cadisegliatin as TTP399, and that's really because, with all of the other studies that we've done and published, TTP399 was the prior name of cadisegliatin. I'll use them interchangeably, and I'll try to highlight that here, but just know that they are the same thing. To understand how cadisegliatin works, you have to understand some biology of glucokinase. Glucokinase is the enzyme that catalyzes the first step of glucose metabolism, or glycolysis, both in the pancreas and in the liver. Glucokinase is a hexokinase, but it has unique properties that allow it to act as a molecular glucose sensor. Specifically, the kinetics of glucose binding for glucokinase is different than for other hexokinases, such that it binds at much higher glucose concentrations.
You can see that in this graph here, where you see that other hexokinases bind at very low glucose concentrations with this blue line, and glucokinase binds glucose at much higher concentrations. That glucose binds glucokinase at high glucose concentrations is really important, because in the pancreas, glucokinase activity leads to insulin secretion. Glucokinase really should only be active during periods of hyperglycemia. In other words, we only want insulin to be secreted when blood glucose is high, because if it's released when blood glucose isn't high, then you'll lead to hypoglycemia.
A second key property of glucokinase is that it is not inhibited by downstream products like glucose-6-phosphate, such that it continues to be active as long as glucose concentrations are high enough. Again, insulin should only be secreted during periods of hyperglycemia and should only stop when that hyperglycemia resolves. Now, because of strong genetic evidence that supports glucokinase's role in glucose homeostasis, like in glucokinase MODY, glucokinase has long been a therapeutic target of interest. But it's been really hard to develop glucokinase activators, in part due to unfettered activation of glucokinase in the pancreas, which leads to insulin hypersecretion and can cause hypoglycemia. That's where hepatic or liver glucokinase comes in.
Hepatic glucokinase has several properties that differentiate it from pancreatic glucokinase. First, hepatic glucokinase has a unique interaction with glucokinase regulatory protein, or GKRP. During periods of euglycemia, meaning when glucose is normal, glucokinase regulatory protein binds glucokinase and sequesters it within the nucleus. During periods of hyperglycemia, when glucose is around, glucokinase binds glucose and undergoes a conformational change, which releases glucokinase regulatory protein and allows glucokinase to go into the cytosol and perform glucose metabolism or glycolysis. Secondly, whereas pancreatic glucokinase is constitutively expressed, meaning that it's always expressed, hepatic glucokinase is insulin-dependent.
Again, we really only want metabolism, glucose metabolism in the liver when glucose concentrations are high and therefore insulin is around. However, when there's inappropriate insulin deficiency, like in type 1 diabetes, the lack of glucokinase expression and activity contributes to the impaired glucose homeostasis, and there's less glucose metabolism and less storage of glucose as glycogen in the liver. Unfortunately, when we deliver, and so we expect that in type 1 diabetes, that glucokinase expression and activity is low, and therefore, glucose metabolism in the liver is also low. So we store less glucose in the liver as glycogen, and therefore, there's less glycogen that's available to be utilized as there is hypoglycemia. Because when people have low blood glucose, the liver-stored glucose is released to respond to that hypoglycemia.
But in type 1 diabetes, it is expected that because of this impaired glucose metabolism, that there is lower glycogen levels that can be mobilized during periods of hypoglycemia. Therefore, if we can selectively restore hepatic glucokinase activity in type 1 diabetes through hepatoselective glucokinase activators, we may have a unique opportunity to improve physiologic glucose homeostasis by increasing liver glucose metabolism and also liver glucose storage, which then can be utilized during periods of hypoglycemia.
To that end, cadisegliatin or TTP399, as you will see here, which I mentioned is the name that we used previously, so I will refer to it here as TTP399. This is a small molecule glucokinase activator that activates glucokinase in the liver but has no activity within the beta cell of the pancreas. Importantly, TTP399 does not disrupt the interaction between GK and GKRP, and thus it maintains physiologic control of glucokinase.
This is important to reduce the risk of liver toxicity. The first study of cadisegliatin or TTP399 in type 1 diabetes was the SimpliciT1 study. This was an adaptive Phase Ib/IIa randomized control trial to test TTP399 in type 1 diabetes. Phase I, or the sentinel phase, was a 7-day dose escalation study to assess safety and determine dosing of TTP399 in people living with type 1 diabetes. After safety was assessed, Part 1 tested TTP399 in 19 adult participants living with type 1 diabetes who were treated with insulin pump therapy and continuous glucose monitors. The primary endpoint was change in HbA1c. When efficacy was assessed, we moved on to Part 2, which tested TTP399 in 85 adults living with type 1 diabetes but did not require continuous glucose monitoring or insulin pump therapy.
So this involved people who were using self-monitored blood glucose as well as multiple daily injections. It is important to understand that SimpliciT1 followed an aggressive treat-to-target design, such that participants had to achieve very tight glycemic control to be randomized in this study. So they had to target a fasting blood glucose of 80 to 130, and that was prior to being randomized. Then during the study, we aggressively changed the insulin to target the same fasting blood glucose of 80/130, but also a post-meal blood glucose of less than 180 with a peak of 200 mgs per deciliter. So this is really, really very tight glycemic control. So any improvement in glycemia that we saw was on top of this very aggressive treat-to-target design and adjustments in insulin.
In Part 1 of the study, we saw significant improvements in glycemia. This, again, was on top of this intensive treat-to-target design and in participants with very good glycemic control with an average baseline HbA1c of 7.3%. As you can see, the treatment effect was a reduction in HbA1c of 0.7% compared to placebo. In Part 2, again, this was a broader population of 85 adult participants on multiple daily injections or insulin pump therapy with or without continuous glucose monitors. We observed a 0.3% reduction in HbA1c compared to placebo. Again, this was on top of an intensive treat-to-target design in participants with good glycemic control with an average baseline HbA1c of 7.6%.
This was consistent with other adjunctive therapies that have been tested in type 1 diabetes, and so we were really excited to see consistent improvements in glycemia. I'll just mention that a 0.3% reduction in HbA1c in T1D really can be clinically meaningful. We were really encouraged by these results. On top of these results, TTP399 was well-tolerated throughout the study. Treatment-emergent adverse events were similar between the groups. However, we found a reduction in hypoglycemia and ketosis events. Post-hoc analysis of hypoglycemia events showed a significant difference with a P value of less than 0.05.
Ketosis events, defined as a beta-hydroxybutyrate greater than 0.4 millimoles per liter at any study visit, were overall few. The study really wasn't powered to assess statistical changes in ketosis events. I think you can appreciate that we saw an early and sustained separation in beta-hydroxybutyrate and though we saw this, we did not perform statistical analysis. Again, we were encouraged because these data were actually consistent with pre-clinical studies that suggested that this could help with ketosis events as well, or glucokinase activation in the liver could help with ketosis events.
What we did next was a phase I mechanistic study, which was an insulin withdrawal test. We were able to show that cadisegliatin, or TTP399, did not increase ketosis risk. This is really an important thing to test because this has been a major barrier for adjunctive therapies in T1D, things like SGLT2 inhibitors, which can improve glycemia but put people at high risk for diabetic ketoacidosis. In this study, we randomized 23 adults on insulin pump therapy to 7- 10 days of investigational product, which was either TTP399 or placebo. Then we brought them into our research units.
We saw them take their daily medication, then we withdrew insulin. These were people who were on insulin pump therapy. They took their medicine, then we disconnected their insulin pumps until they met stopping criteria. As you can see, there was no difference in the rise in glucose or the beta-hydroxybutyrate. This again is really encouraging and suggested that cadisegliatin does not increase the risk of diabetic ketoacidosis. We were really interested to see that there were actually signals for a reduction in diabetic ketoacidosis risks because there were 42% of participants randomized to placebo who met criteria for mild DKA, whereas none in the TTP399 group or the cadisegliatin group who exhibited mild DKA.
We don't have time to talk about this a lot, but these data again align with pre-clinical studies that suggested a potential role for glucokinase activation, hepatoselective glucokinase activation in reducing ketosis risk. Overall, really just suggested that cadisegliatin really does not have any evidence for increasing diabetic ketoacidosis risk in people living with T1D. Taken together, these data demonstrated that cadisegliatin has a potential to improve glycemia and also reduce hypoglycemia, and there's really no evidence of increased risk of ketosis. What comes next? Here is the ongoing CATT1 study. This recently completed enrollment, which we're very excited about. The goal was to randomize 150 participants, and you can see here that we enrolled 166 participants across the country.
These individuals are randomized 1-to-1- to- 1 to 800 mg of once daily TTP399 or twice daily TTP399 or cadisegliatin, or insulin alone placebo. People are randomized after 8- 10 weeks of screening and lead-in, which again involves this very aggressive treat to target design, so adjusting insulin to target very tight glycemic control. CATT1 is following the same aggressive treat to target design. Any improvements that we see will be on top of this aggressive treat to target design. Randomized participants will be treated with the study medication, either the placebo or either of the two doses of cadisegliatin for 26 weeks. The primary endpoint of this study is incidence of level 2 or level 3 hypoglycemia, and there are key secondary endpoints, which includes change in HbA1c, so we're looking at glycemia.
This is really important that we're looking at glycemia in this aggressive treat to target design, so any improvement will be above really tight glycemic control that's trying to be achieved in all groups and blinded on both sides. We'll use a CGM to measure the reduction in hypoglycemia events. This study was really informed by FDA advice, and in accordance with the FDA draft guidance issued in 2023 on diabetes-related clinical trials. We're excited to see what we see. I would hypothesize that we will see a reduction in hypoglycemia as well as an improvement in glycemia.
Importantly, this improvement in glycemia will be coupled with this reduction in hypoglycemia, which is really the goal here, to be able to achieve tight glycemic control, as Martin Lafontaine was saying, kind of having these guide rails, so that we can achieve tight glycemic control without increasing hypoglycemia risk. That's what we're looking forward to seeing. The next study that is also in startup and actually have a number of people in screening, will also explore the use of cadisegliatin in people using automated insulin delivery, which Dr. Boeder spent some time talking about. This is new technology, and because the technology is so powerful, the population of people using automated insulin delivery is growing enormously. It's really critical that we assess the potential of cadisegliatin to improve outcomes in people using automated insulin delivery using this new technology.
This study will enroll 40 people using automated insulin delivery, and all participants will conduct two six-week periods, one with insulin and placebo, and one with insulin plus 800 mg of cadisegliatin. The order of these two six-week periods will be randomized and double-blinded. The primary endpoint in this study will be time in range and will be collected in the final two weeks of each treatment period. Other important endpoints will include other CGM-derived metrics like time above range and time below range, as well as time in tight range, which is a slightly tighter goal that we will look at to see if there's any improvement in that time in tight range. We'll also look at glucose excursions after a mixed meal tolerance test.
These are juices or mixed meal therapy, protein and fat, a mixed meal that people will drink, and we'll look and see how much excursion these individuals experience depending on which agent they're on, placebo or cadisegliatin. These data will help inform the design and conduct of future phase III research. What I think we can say, taken together, these completed studies support the role of a hepatoselective glucokinase activators for improving glycemia with a reduction in HbA1c between 0.3% and 0.7%. There's really no evidence that this glucokinase activator, cadisegliatin, has any increased risk for diabetic ketoacidosis, which is really important in people living with T1D. It also supports the role of a glucokinase activator with having potential to improve risk of hypoglycemia, and we currently have a phase III study that will explore this hypothesis more.
Finally, this is a medication that's an oral medication that's very well tolerated. We're really excited to see where this medication can go and whether it has the potential to improve outcomes in people living with T1D. I'll go ahead and pass it back. I will look forward to hearing the questions.
Thank you so much, Dr. Klein. Thank you to all of our speakers. Investigational program is cadisegliatin, as you heard, which has been granted FDA breakthrough therapy designation and is in phase III development. We recently completed enrollment in our phase III CATT1 study, and we expect top-line results in mid 2027. If successful, cadisegliatin has the potential to become the first oral adjunctive therapy for T1D in the U.S. About 75% of people living with T1D in the U.S. do not reach the ADA recommended A1C target of below 7%. According to the 2026 Joint Consensus Report from the ADA and the EASD, hypoglycemia is the most important limiting factor in the glycemic management of adults with T1D.
Technology has made real progress, but today's tools have not closed the gap, and we believe that this gap represents both a meaningful clinical need and a significant opportunity . Our team is made up of seasoned executives from Biopharma who have a strong track record of advancing novel therapies in metabolic diseases, diabetes, and more. They've taken on difficult challenges before, and they bring that experience and a deep commitment to advancing cadisegliatin. Our balance sheet is strong. We ended the second quarter with $86.6 million in cash, which provides enough runway to fund operations well past the CATT1 top-line readout.
Finally, while cadisegliatin is our focus, we have additional clinical stage assets across several indications and at various stages in development. These assets present opportunities for significant non-dilutive funding and provide additional ways to create value beyond our lead program. Next slide, please. We'll spend the last few minutes with some Q&A. Joining me for the Q&A session are our featured guest speakers that you've heard from, Dr. Schafer Boeder, Dr. Klara Klein, Alisa Weilerstein, and from vTv, Martin Lafontaine, our Chief Commercial Officer, Dr. Thomas Strack, our Chief Medical Officer, Dr. Michael Tung, our Chief Financial Officer, and Dr. Carmen Valcarce, our Chief Scientific Officer. I'll turn it over to the moderator, Tara, please, to now begin the Q&A.
Great. Thank you, Paul. Yes, so at this time, we'll be conducting our Q&A session with our speakers. To our analysts joining us live, we kindly ask that you limit yourself to one question and one follow-up, and to direct your question to the appropriate speaker. Please hold for a brief moment while we poll for questions. Our first question comes from Ritu Baral at TD Cowen. Please go ahead, Ritu. Ritu, you might be on mute.
I am on mute. Apologies. Good afternoon. Thanks for taking the question, and this very informative overview. Paul, I guess for you and the experts on, how would you define successful measures for CATT1 final data in mid 2027? What are you looking for, especially as you think of it in the context of the market research that you presented early on in this event?
Yeah, thanks for that question, Ritu. Why don't I start with Thomas, please, and then maybe over to Martin.
Yeah, thank you. The CATT1 study is designed and powered to demonstrate a 30% reduction in hypoglycemia across the six-month period. That's clearly a benchmark for us to achieve. We also have significant power to demonstrate at least non-inferiority in A1C. You have to remember that FDA, of course, wants us to reduce hypoglycemia without sacrificing glycemic control. I think these are the key points that we need to achieve in the study to claim success.
In your profile, you also had 5% reduction in insulin use. How important is that to, I think, the commercial profile?
I can take that and maybe Martin can supplement. We saw some insulin reduction in about 40% of subjects who participated in the SimpliciT1, the phase II study that Klara just presented. I think it's important for people with type 1 diabetes to reduce the insulin whenever possible. High insulin concentrations in a peripheral bloodstream can enhance hypoglycemia risk. They also have other cardiovascular risk factors, so reducing insulin is actually of some health benefit. In addition, it might be easier for people with type 1 diabetes to maintain or even reduce their weight. Martin, do you want to add anything?
Yeah, maybe just to add to that, thank you for asking, Ritu. It is seen as a side benefit. I'll say the core of the benefit is really in the hypoglycemia reduction. Reduction in insulin consumption, which is linked to weight, can really be seen as a side benefit, but I wouldn't put it at the same height at all as the primary benefit of hypoglycemia.
Understood. If I can sneak one last one in here, are there any endpoints in the design that are, I guess, PRO, patient-reported in nature, as you talk about sort of this mental burden of potential hypoglycemic episodes contributing to anxiety. Does the trial structure capture any of that, even if it's not pivotal in nature, it certainly could be used for the diabetic community and the clinical community to underscore the importance of the potential data?
Yes, that's a very good question. We do have several instruments in the CATT1 study to assess the impact of cadisegliatin on quality of life, fear of hypoglycemia, burden of hypoglycemia. We also have a couple of measures to look at hypoglycemia and awareness. So it's actually a very broad PRO program to capture potential benefits of prolonged cadisegliatin treatment, and certainly are committed to continuing that in our future trials.
Thank you.
Thanks for the questions, Ritu Baral. Our next question comes from Kambiz Yazdi at BTIG. Please go ahead.
Hi, team. Thank you so much for the very informative presentation. Maybe my first question for the doctors, what magnitude of reduction in level 2 and level 3 hypoglycemic events would you consider clinically meaningful? Does that threshold depend on the accompanying HbA1c?
Maybe Klara or Schafer, you want to take. Thanks, Schafer.
Sure. I will start that and maybe Dr. Klein can weigh in. This is going to sound like a bit of a cop-out, but any reduction in severe level 3 hypoglycemia events is clinically meaningful and clinically significant, because any one of those events can lead to an ER visit, a hospital stay, or potential death. I cannot put an exact number on that, but any statistically significant decrease is also clinically significant. I think for level 2 hypoglycemia, there probably is a number that we could put on it.
I do not know, maybe Dr. Klein can say something to that, but I think that in terms of the burden of hypoglycemia and the risk for subsequent hypoglycemia, we can see that any reduction in those values can actually improve outcomes moving forward and reduce the risk of subsequent hypoglycemias. The numbers do not have to be drastic to basically improve outcomes and reduce the risk of subsequent lows. In relation to A1c, I think if we had to give on the A1c in order to reduce hypoglycemia, I would still, in some cases before that, in particular, if we see a reduction in severe hypoglycemia, that is just an acute, dangerous condition that we need to prevent really at all costs.
I also think the data thus far would suggest that we will not have to make that decision. I think that the A1c will also support this medication based on the data that we have so far. I will be very interested to see how that shakes out.
Yeah, I'll just add, I would say the same thing, which is that any reduction is meaningful. I take care of loads of people who have T1D. I personally don't have T1D, but it's always so It's amazing to hear people talk about T1D. We just heard Alisa talk about this disease. The burden is so enormous. The idea, you talk to your colleagues, your friends, they're running out of the house and their blood glucose is 65. Maybe they're not recording that or reporting that, but that means that they can't get their kid to school on time because they have to run back into the house and get a gummy or get a drink of juice. I think we cannot overstate how significant it is to relieve the burden at even level 1 hypoglycemia.
Relieving the burden of giving someone the sense of security that they are going to be able to give some insulin and not have a severe hypoglycemic event. These are really, really meaningful outcomes to individuals, and I'm hopeful and optimistic that we'll see this on the population level, right? We're going to see improvements that we can say this is statistically significant. This is not just about that, right? It's about the everyday burden of living with T1D, and even what seems small to someone who doesn't have T1D may be enormous to someone who does. It's hard to put a number on it, but I think when you take care of people or you have a family member or a friend who has T1D, you recognize that any of these changes are really important.
Thank you so much. Maybe one follow-up question for the company, maybe directed to Martin. Which T1D patients do you think could be initially prioritized for cadisegliatin? Those with recurrent hypoglycemia, impaired awareness, or maybe patients with above average A1C, or do you see this as a broadly applicable therapeutic initially? Thank you.
Thanks for asking, Kambiz. I think the data will also speak, right? We'll see where the data brings us. But at a high level, you look at those four populations, and they are four population with heavy burden when it comes to hypoglycemia. Frequency, severity, what you see, what they feel, and then there's underlying, what you don't see is that feeling of not feeling your lows and what it can create from an anxiety standpoint. Same thing for people who are already anxious because of past events or just because of their personality.
So when we look at endocrinologists and how they look at it was pretty consistent across the board that in those four target populations, the burden is there, and their willingness to recommend a therapy that would actually help to reduce the risk of hypoglycemia was pretty high and consistent. To your question, we'll definitely do more work to scrutinize that, but a high level, I'd like to say that these four population are very much priority populations.
Thank you so much. I'll hop back in the queue.
Pleasure.
Thanks, Kambiz. Our next question comes from Mike DiFiore at Evercore. Please go ahead.
Hi, guys. Thanks so much for taking my question and for hosting this event. Just two from me. For the CATT1, for the phase III CATT1 trial, just curious to see how will dropouts and missing data be handled. My second question is this, what if any, what are the safeguards that are available to mitigate the risk of the CGM device falling off, if that's even possible? Thank you.
Thomas, do you want to take that?
Yeah, I can take your question. We have been in intensive discussions with the FDA on how to handle missing data, and I think we are approaching an agreement how we are going to do this. There are established methods to do so. I cannot go into much detail about this right now, but clearly, we're going to try to use all data as much as available point in time, so this might be a very minor problem for this trial. But certainly, it's a good practice for our futures trials to understand how we approach this issue.
Great, and just the safeguards to mitigate the risk of the CGM falling off?
Well, every subject or every participant in the study gets a complete kit from the company that provides the CGM devices to, for example, safeguard against easily falling these off when taking a shower, for example. We are providing participants with ample supplies to make sure that this risk at least is mitigated as much as possible. Of course, it does happen, but we always have sufficient replacement devices at our study sites to make replacements available very quickly.
Excellent. Thank you.
This has not been a frequent issue so far.
Got it.
Great. Thanks for the questions, Mike. Our final question comes from Adam Walsh at ROTH. Please go ahead, Adam.
Hi, thanks. Can you hear me?
Yes.
Yes.
Okay, perfect. Thank you very much for doing this great event. This was really helpful, and I appreciate it. A couple of questions. Type 1 patients are already juggling a lot with their routines and medications. Is adding a pill a barrier, or is it easy compared to everything else they do? Does once versus twice a day matter much to them? I will point that one at Dr. Boeder and Dr. Klein, and of course, Alisa as well.
I'd love to hear Dr. Klein and Alisa's feedback on this question, but it's a good question. As someone who's studied T1D for many years and has done many different clinical trials, I would say I'm not concerned about that additional burden when there's a true benefit. Actually, the opportunity to take a pill for T1D, which does not exist, there is no such thing, is quite extraordinary and quite exciting, I think, for many people living with T1D. They would love to take a pill rather than have to take an additional shot or do something else throughout the day.
Anecdotally also with having been involved in, I think, now three trials, including two ongoing with this exact agent, people are very excited to be on it. Again, that's anecdotal, but it has not been shown to be a particular burden. People with T1D, as you said, have so many things that they're used to doing, and compared to giving insulin injections and keeping up their pump and keeping their CGM on and dealing with all this other stuff, this is actually very low-hanging fruit for them and pretty easy and pretty accessible. That has not been an issue. In fact, most people are quite excited to be on it. I would also say we did some informal data at UCSD.
We ran some surveys asking that question actually specifically not related to this medication, but just in general, to our participants with type 1 diabetes. We sent this out to a large group of people living with T1D and asked, "Would you take a pill once a day if it could do X, Y, and Z?" One of the things was lower your hypoglycemia burden, one of the things was improve your glycemic control, et cetera, and would you be willing to add a pill to your regimen to do those things? I don't have the numbers ahead of me, but the vast majority of people with T1D expressed that they would have no concerns about adding a pill if they could achieve those things.
I think once a day is always easier and better than twice a day. Again, I don't think that the burden is as much of an issue, but you have to worry about remembering to take it and the compliance and all those things. That's the short answer on that one. If we get away with once a day, that's good. But if it's effective at twice a day, I think people with type 1 diabetes would be happy to take it.
I am going to defer here and let Alisa tell us what she thinks.
Everything that you said just now, Dr. Schafer Boeder, is absolutely true. I would be thrilled to take something that would make glycemic control much easier because, again, for us, all the equipment, that is not really the burden, it is the management and it is the mental gymnastics. That is the real burden, and all of the anticipation. The other thing which I am glad I got another chance to speak to you is, the rebound effect of hypoglycemia that we deal with. It is the bouncing around. The hypoglycemia, of course, and all of the risk associated with it and all of the physical effects, this is extremely important, and all, but, for example, I know I experienced it just the other day.
I got low in the middle of the night and I popped the glucose tablets, and of course, personally, I tend to feel my lows very intensely. Even after I have risen enough, I still have the shakes and the kind of brain fog and all of that. I have to tell myself to stop eating. But even so, my blood sugar skyrocketed to like 250. Then I had to wake up early, of course, to take the kids to school, so around 6:30 or so after having kind of a miserable night.
Then by the time the algorithm kicked in, the Control-IQ, so that when I woke up, I was 125, but I had gone from 48 to 250 and then back again, and that is no fun at all. If there is a pill that would reduce this significantly, this would be an-
Just add, I guess, that I think all of this is individual, right? I just think it depends on the person, but as a provider, there's just no reason to think that if there's something that you can help reduce these risks, there's just no reason that we wouldn't offer it because hypoglycemia is such a problem. A patient taught me about the glucose coaster, this thing that you're talking about, where you go down and up and down and up. If we can make that better, there's no reason not to offer it to people.
It still remains amazing to me that until now there has been no concurrent therapy along with insulin. This is pretty amazing in the past over 100 years.
Yeah, it's true.
Excellent. If I could just ask one more as my follow-up. I'm curious for Doctors Klein and Boeder, which number do you actually watch more these days, time in range or A1C? And if a drug improved time in range but only moved A1C a little, would that be enough for you?
Sorry, just to repeat the question. The question is, if it improved time in range but not HbA1c, would that be enough?
It only moved HbA1c a little, but improved time in range.
Yeah. I think that Dr. Boeder probably can speak to this. I know that they ran another study where this was true. It's often that you see time in range improve, but you don't see as much in HbA1c. I do think that the standard now is we try and correlate our CGM to HbA1c, but often rely mostly on CGM because it gives us just so much more information about what's going on throughout the day. Someone can have an HbA1c of 7.5 but have a mixture of 400s and 50s. It's an average. The CGM, it just is much more rich information. So yes, I think again, all of this is in context, right? If you're improving time in range by reducing lows, that's huge.
If you're reducing lows, it may mean that the HbA1c kind of stays the same because it's all of an average. So I guess my answer to that is yes, and it depends. We like to see everything get better. But I think that if we look at time in range and it gets better, then that I think a lot. We use point of care HbA1c. Those also have error as well. So we try and take everything together, but I think improvement in time in range and reduction in time below range really would be very meaningful.
My short answer is yes, I would very much favor an intervention that improved time in range, even if it didn't have a large change in A1C. I use time in range much more. I look at the CGM metrics first and the A1C metrics second because, as Dr. Klara Klein said, there's so much more information there. To Alisa's point, the A1C does not in any way capture the ups and downs and highs and lows and rebounds and all of this other burden that at least the CGM gives us some picture of the experience, and the glycemic variability, which is its own outcome metric that we can glean from CGM and not from A1C. I think the A1C still is important, but we know there's a lot of problems with A1C.
If you really want to know what the average blood sugar is, look at the average blood sugar. You can get that from the CGM, and then you can look at the time in range. I think it's a much more powerful tool.
Great. Thanks again.
I just wanted to thank you all for your great questions. We're just a couple of minutes over time, and for your time today. Once again, I'm so grateful to Dr. Boeder and Dr. Klara Klein for generously sharing their expertise, for Alisa for sharing her personal experience, and my entire vTv team for pulling this whole event together. For all of those of you that joined us for these 90 minutes, thank you so much for your attention and for your engagement, and we'll be hopefully talking to you all again soon. Thanks again.