Thank you and welcome. Thanks for coming. Thanks for joining us. We really try to make it interactive and first, before we start, I want to introduce our speakers today. So I'm Thomas Biber. I'm from the Medical University in Graz in Austria. I have the pleasure to chair this session. On my right side, there is Edda Cengiz. She's Professor of Pediatrics of the University of California, San Francisco, and they're Director of the UCSF Pediatric Diabetes Program. On the other side is Deben Steenkamp, or Stan Kemp. He's Director of Clinical Diabetes in the section of Endocrinology, Diabetes, and Nutrition at Boston Medical Center at Boston University. So together we would like to discuss with you about this novel treatment options that are currently announced and that are approaching us. So in the first part, we would like to address some of the barriers to appropriate basal insulin therapy initiation. And I want to start here that highlights the fantastic development that we have seen in the last 25 to 30 years when it comes to basal insulin. So many of us might remember still the time when we were using MPH insulin. You had to give this twice daily. You had to resuspend it and resuspension together with the crystal formation is one of the reasons why MPH insulin was associated with a rather high frequency of hypoglycemia. Then first-generation basal insulin analogs like insulin Galgene or insulin Detemir were introduced. And so the second generation with insulin Galgene U300 and insulin Deklotec in U100 and U200 concentration. For basal insulin therapy, we need a flat profile. We need a profile with low variability. And the question is now what kind of insulins might we have in this third generation basal insulin analogs? How long can we stretch the duration of time to action? Despite the improvements and the once-daily basal insulin that we are using currently, there are still some challenges that remain. Some of them have been or many of them have been mentioned by yourself just in the word cloud. So dose administration, the timing and the multiple injections that patients need, the risk of hypoglycemia that's linked with insulin therapy, the frequent dose adjustments, the high number of injections. When you have a daily basal insulin, it's 365 days per year where you have to inject your basal insulin. Adherence, a major challenge for our patients. We will come back to that. Weight gain, fluid retention. And then last but not least, only a small subset of our patients between five and 45, maximum 50% of our patients are achieving the desired gasemic controls when we look into real-world data. So there is room for improvement when it comes to these therapy options. We also should listen to what patients are saying. So these are true patient statements and they, for example, highlight the weight concerns. I've recently been put on insulin and put on 28 pounds. It's making me more miserable than diabetes does. Any advice on shifting insulin weight? This is one of the problems we know quite well in our patients. Another concern is related to dosing and injection challenges. Ken says, yesterday I screwed up my basal injection and lost some of it, probably about half of it. I did not try to take any more because I didn't know how much I got. So those are challenges that our patients are facing and this is a survey that has been published recently and it shows the prevalence of insulin wasting. And you can appreciate that only one third of, roughly one third of the patients never is wasting any insulin. That's pretty common in 40 to 50% that more than once per month there's insulin wasting. And there's also prevalence of shorting. So reducing the insulin dose because, for example, there's not left enough in a pen for the next injection. Then patients are shortening their insulin injection and this all adds up to the problems we have then with the glycemic control. And this is also associated with some stress. Another survey or the same survey that was looking into those challenges and people find it stressful when, for example, they throw away leftovers of long-acting insulin when they realize they have to inject twice because the leftover does not have enough units. Sometimes they are not injecting the rest of the insulin and they realize that two injections are needed and then people stay away of that second injection. So this is a pretty common phenomenon when it comes to basal insulin use. And healthcare professionals know that well and they contribute a substantial stress for their patients when this is an issue. And then another problem we have are missed doses. So this is the percentage of people who miss their insulin dose and some of the reasons, the main reasons. So almost 40% of the people miss at least one dose per month. When they have more injections, this is more likely, which is easy to explain. It's almost 50%. And the main reasons are they are forgetting, they're falling asleep or they are too busy to do their insulin injections. So there are also provider level barriers that contribute to underuse of insulin. So we perceive these patient barriers. There's concerns regarding patient acceptance, the fear of hypoglycemia, the perceived complexity of insulin regimens and time constraints. And unfortunately, there's something what we have to call therapeutic inertia. So many of the patients do have an HP1C of around 8% for the last three to five years before insulin is initiated. The current guidelines also might contribute to a negative perception like insulin is the last resort. But sometimes there's also a lack of team experience and confidence in treatment intensification for our patients. And then incomplete knowledge of underlying pathophysiology also might play a role. Again, we are listening to our patients. So Peter says, my doctor tells me insulin is a last resort. Due to when you take it, your body stops the production of your own. So once you start on insulin, you will be dependent on it. This is a misconception that is quite common, unfortunately. And we would like to discuss a case together with you. So Mr. Smith is a 64-year-old man with a history of type 2, diagnosed 10 years ago. He presents to his physician's office for a routine follow-up. His current medications include metformin, twice daily, and tripecide daily. And his last HP1C was 8.5%. Due to his medication regimen and lifestyle modifications, Mr. Smith's blood glucose control remains suboptimal, as evidenced by his elevated HP1C level. I'm going to play the role today of starting off some panel questions for my colleagues and then I'll jump in as well. I'm going to pose this to Erin Thomas here. So here is a patient in that situation. And so in the light of the challenges that we've just spoken about related to this patient, and now we have all these fancy new medications that just keep getting more and more, whether we can get them or not, it's a different question. Is there still really a role for basal insulin? Why not? I mean, I think you made an excellent case. You know, we need to know more about this patient, you know, what's going on with C-peptide. If this patient has a very high BMI, I might go towards like GLP-1, but you can always add something depending on what's going on with the situation and the presentation. So I think there's no one straight answer, but definitely basal insulin might be an option for this patient depending on what's going on. Is it a catabolic stage? Do we, what's going on with C-peptide? And I think that insulin, basal insulin will be an excellent choice. I think the weight is always a very good indicator. If someone is likely to need insulin, the more weight loss occurred in the past or the less obese someone is, the more likely basal insulin is a valuable option. There's no strict rules for that, but I think it's a good clinical indicator for us. So if we see a type 2, a lean type 2, it's very likely that those patients will need insulin. And sometimes we start pretty late because we have so many treatment options. We have all mentioned them. They are fancy. They are nice. They are talked a lot about. So sometimes we are forgetting that insulin, if insulin deficiency is the driving cause for the hypoglycemia, that insulin is a very good candidate. And the only thing I would add, I think to our two colleagues over here and at the back, just to those two comments, I think you're right. You really need clinical data and then there's a fair decision-making process with patients. And for some patients, basal insulin may be something that they prefer, depending on what their comorbidities may be, if they have gastroparesis or something else, a GLP-1 is going to be a hard cell potentially, or they have significant issues there. And then also a duration of diabetes. If they've been living with type 2 diabetes for 30 years, are we really going to have much beta cell benefits in terms of trying to ask the beta cell to do more when the beta cells are already tired or no longer there? Let's listen again, what patients are saying. So Kyla says, I'm type 2 and on fast-acting insulin with meals and a long-acting insulin at night. I feel so much better in myself. Sugar levels are under control now. I've tried lots of different tablets and nothing helped. Just nasty side effects from them all. So this is one of the typical patients where insulin or starting insulin therapy sometimes is perceived as a relief from diabetes symptoms, many, many medications or medications where they have the feeling they are not working. And there are good reasons why we sometimes don't realize early enough that someone needs insulin. And this slide shows us the three major contributors for hyperglycemia in type 2 diabetes over the time. So when someone starts with normal glucose tolerance and then develops impaired glucose tolerance and insulin resistance, this insulin resistance mainly driven by body weight remains. And because there is impaired glucose tolerance, we do have already some of a beta cell dysfunction. Usually when our patients are diagnosed, and this comes from UKBDS data and from many other cross-sectional data again and again, a diagnosis typically roughly 50% of our insulin secretion capacity is already impaired or lost. And over time, when then patients are treated and patients are entering a later stage, insulin resistance remains. But with increasing beta cell dysfunction, of course, also hepatic glucose production increases contributing to the hyperglycemia. And then it's definitely time to think about insulin and basal insulin as a very good starting point for our patients. So there is also good pathophysiological reasoning that at some stage we will need insulin. So let's move closer to the topic. What are new third generation basal insulins? What is to be expected? So the idea is to have an extended time action profile that allows for once weekly insulin administration that should more closely mimic endogenous basal insulin distribution profiles. For that, we have to develop a once weekly basal insulin with a long and flat exposure profile, control tissue distribution properties and attenuated potency at the insulin receptor. And we will come back to that point. We would like to have a reduced variability by controlling fluctuations in the glucose levels during this week and maintaining an acceptable and manageable hypoglycemic profile. There's one clear limitation when we discuss an insulin given once weekly, and that's the fact that it's not easy to adapt insulin requirements fast because you have to wait a week before you have to make your next dosing decision. However, and this is important when you talk to patients, expectations are high from the side of the patients because they prefer definitely fewer injections. And the breakthrough in GLP-1 agonist therapy is the once weekly GLP-1 and many of the patients are thinking this once weekly rhythm already. And the idea is that this once weekly insulin might improve acceptance, adherence and even persistence on therapy. So when it comes to what kind of clinical parameter do we need? So pharmacology there is needed. So the PK and PD pharmacokinetic and pharmacodynamic profiles of a basal insulin after a single dose, there are different parameters. There's the injection time and there's a time to the maximum concentration. And then there's the terminal half-life for the PK. And then the duration of action is the time in which we can expect a glucose lowering effect, which is usually measured in the phase one trials with the glucose infusion rate in the eukalycemic GAMP study. And the peak to trough ratio is also an important feature because it tells us how much insulin concentrations differ between the peak concentration and the lowest concentration before the next insulin dose is injected. So there are some limitations for our daily basal insulin analogs. And one problem remains, of course, when we're using insulin once weekly or once daily, that is the fact that we under-insulinize our liver because when we inject insulin, it enters first the periphery and not the portal circulation and is not seen by the liver first, like with our endogenous insulin secretion coming from the beta cells. On the same time, we tend to over-insulinize the periphery, which then leads to the tendency of weight gain and the increased risk of hypoglycemia. So for clinically, the attributes for once weekly insulin therapy, we would like to have an improved or at least similar glycemic control as we have with once daily insulins with a low hypoglycemic risk, a reduced treatment burden with less insulin injections, maybe an approach to easier to overcome the therapeutic inertia on both sides, on patient side and caregiver side. On a molecular level, we would need a long half-life, at least for a week, a stable pharmacokinetic profile with low interpatient and intrapatient variability and a slower clearance, which will contribute to the duration of action. And we've seen that before we moved from MPH insulin to insulin given once daily, like insulin Declotec or insulin Glargine U300. They cover nicely the insulin need over a day. But when you stretch that for a full week, you need a much longer duration of action that we have to achieve. And we need, therefore, a very flat pharmacokinetic profile with a reduced variability, which then leads to the reduced injection burden. So what innovations are on the horizon and I'm moving right into introducing to you the new basal insulins that are currently under development or will be available soon. So there are currently two compounds. One is insulin Icotec and the other is insulin Fcdora Alpha. So let's start with insulin Icotec. It has a side chain with a 20-carbon fatty D-acid. And this leads to a very strong albumin binding and albumin, the circulating albumin in plasma, but also the albumin in the interstitial fluid has the depot function for that insulin. It also has some changes in the insulin molecule that reduces enzymatic degradation. There's a reduced insulin receptor-mediated clearance, which also prolongs the duration of action. And the time action profile has a half-life of approximately eight days. And this supports a once-weekly dosing in humans. Phase three is complete. It has been approved in Canada and Switzerland already for type 1 and type 2 diabetes. The European Medicine Agency recommended approval recently and FDA, you might have heard the news, currently does not recommend it or recommend it against the use in type 1 diabetes. And we will come back to that in a minute during our presentations. The second one is Insulin Fc-Tora-Alpha or Insulin Fc-Tora. This is a very different molecule because it's a novel single-chain variant of an insulin that's used on the Fc domain of a human immune globulin IgG. It's a homodimer. It has a reduced insulin receptor potency, but still full agonism. And the time action profile is approximately 17 days and supports once-weekly dosing in humans. And this insulin is currently in phase three trials. And Eda will present the latest data on those, both insulins. So when it comes to insulin ecotech, you see here the molecular structure. As mentioned, it has a C20-icosamphatidic acid that binds to the albumin, half-life of eight days. But it retains the same biological properties as natural human insulin when it binds to the receptor. So after injection into subcutaneous tissue, the diene monomers are then absorbed via the endothelium and bind to the circulating albumin. And how the dosing and the steady state, the mode of action works is indicated here. So with our first injection, first the insulin ecotech is in the interstitial compartment of the subcutaneous tissue, then slowly enters the circulation, binds there to albumin as well as it binds to the albumin in the target tissues, in the intracellular space of the target tissue. And finally, it binds to the insulin receptor, activates insulin receptor, leads to glucose uptake with some clearance. Then after a week, when you give the second injection, the number of molecules that are in the interstitial compartment that are circulating is increased. You have more effect in terms of glucose uptake. With the third injection, we are slowly achieving or coming close to a steady state. We can say that after the fourth injection, when we have the same doses, we achieve steady state within three to four weeks. Or if we can change that and achieve a steady state much earlier by using a loading dose, which is the black line, by, for example, doubling the insulin dose in the first injection, when you switch someone from one insulin to this new insulin, you're achieving steady state conditions already from the beginning on. This was the mode of action for insulin ECODEQ. When we look at the BKBD profiles of week five, on a once weekly dosing, you can appreciate that there's a nice dose dependency and very flat profiles for many, many hours, which represents a week. When we look at the glucose lowering effect, the pharmacodynamics effect of insulin ecotech. You can see it's more or less equally distributed and the slightly higher insulin levels we achieve or we get on day two and day three are actually the reason why in type 1 diabetes, titration of that insulin might be a little bit more tricky than compared to type 2 diabetes. So the second molecule is insulin F-Citora. As mentioned, it's a human IgG F-C domain that's fused with a single-chain insulin molecule that has some changes in the molecule to again protect it against enzymatic degradation. The F-C domain then binds to the F-C receptor and helps to have a prolonged half-life. The half-life of this insulin is 17 days. And therefore, this formulation is compatible with a single use or multiple use devices and can be formulated with incretins together as insulin ecotech can do. And despite this very different insulin molecule that can see here, data have shown that it has a low immunogenicity risk. So there is no increased formation of antibodies in that molecule. So how is here the mode of action? How can we achieve this very long half-life? So when you inject this insulin into the subcutaneous tissue, it enters the blood vessel in the circulation there. Monocytes and endothelial cells internalize via endocytic vesicles this insulin. And this is then recycled into the circulation. That means that the monocytes and endothelial cells are the compartment for that insulin via the neonatal F-C receptor, which stabilizes the insulin action and gives us this very long pharmacokinetic profiles that we see with that new insulin. So dosing works here when we have, when we inject the first dose, it enters circulation and reaches the target tissues where it binds to the insulin receptor, has some receptor clearance. When we have the second injection, more insulin molecules are circulating, more and more are achieving or reaching the insulin receptor in our target tissue. And after four injections after a month, we are getting closer to a steady state level. After eight weeks, we fully achieved that steady state. And when you use a loading dose, as you would expect for the other insulin, as for insulin ecotech, we're achieving this steady state definitely early after two to three weeks. This is reachable when we use a loading dose. Okay, and how do the pharmacokinetic profiles? So this is a single subcutaneous dose. We see a very nice dose response. Please note, this is a log scale on the y-axis. And after six weeks, we have very flat PK profiles with insulin F-sitora at different concentrations as indicated in this PKBD study. Both insulins, both new basal insulins can be combined with GLP-1, can be co-formulated. So there will be a co-formulation available in the future. And why do we need, or why do we think about this co-formulation? Well, there's complementary actions for basal insulins. So the standard action of basal insulins are inhibiting hepatic glucose production and the insulin effect on the periphery and adipose tissue and skeletal muscle. And when we add that with a GLP-1 receptor agonist, we have the decreased energy intake due to the appetite regulation with increased satiety. We have the glucose-dependent insulin secretion, the glucagon secretion, and the delayed gastric emptying or the GLP-1 receptor agonism that we need. And when it comes to the ideal balance between efficacy and safety, so with basal insulin, we have a very good effect on HP1C and fasting plasma glucose with very little effect on postprandial glucose. When we have a GLP-1 receptor monotherapy, we can achieve the same glucose lowering effects for fasting plasma glucose, but also for postprandial glucose because of the insulin secretory effect of GLP-1. And when we have a combination of both molecules, we expect to have an even more pronounced glucose lowering effect by having a substantial effect on HP1C and fasting plasma glucose and postprandial glucose. Whereas when it comes to side effects with insulin monotherapy, weight gain and hypoglycemia, clearly one of the side effects when it comes to GLP receptor agonist monotherapy, there's the benefits in weight loss. There's a low risk of hypoglycemia, but still the gastrointestinal side effects. And if we combine this in one injection, we might have a weight neutral or a slight weight loss effect despite introducing insulin with a low risk of hypoglycemia and less gastrointestinal side effects. And Eicosema is the first fixed combination that is currently under development. So it's combining the once weekly insulin Eicotech with the once weekly Semaglutide. There's 700 units of insulin and two milligrams of Semaglutide in this preparation. And it will allow a maximum weekly dose of 350 dose steps, which is 50 units of daily insulin given once weekly with insulin Eicotech. And that corresponds to one milligram of Semaglutide. So for you two, so how does the FACOM kinetic profile of once weekly insulin influence its suitability for different patient populations, such as those with type one or type two? And why do we need a loading dose? And I think maybe this is a good place for us to talk a little bit about what happened this week with the FDA in terms of type one, as I'm sure many of you have that question. Edda, do you want? Sure. So many of our patients, you know, they're struggling with insulin injections, being compliant with insulin injections. So if you can achieve decent insulin glucose lowering action by injecting once a week, I think, and if your pharmacokinetics, you know, supports that, I think it would be ideal for many patients for type two. And I manage a lot of adolescents with type one and 70% of them are not in good range. And we keep admitting them in DKAs. And I know I'm well aware of the FDA advisory panel decision, you know, comments. But I think there is a huge role of a weekly insulin for type one patients too, provided that you select your patient well, and then you also have some safety, you know, next like using CGM with alerts. I think there's a huge, you know, role for these insulin in my view as a clinician. And I think the loading dose, Thomas explained the pharmacokinetics and pharmacodynamics of iCodec and F-sutura so well. You know, these insulins of pharmacokinetics, you know, how your body treats the medication and pharmacodynamics is how glucose levels respond to insulin. And, you know, in this case, you saw that you need that loading dose to achieve a good level in blood. Once you're there, you're at the therapeutic, you know, range, so you're good. Then your insulin is gonna work well. I think that's one of the reasons we need that loading dose for these weekly insulins, just to get there and to prevent some hyperglycemia, early hyperglycemia, when we're switching our patients from, you know, once daily to weekly insulins. So that's my take. Yeah, thank you. And I would like to add here that when you start a patient on insulin, a type 2 diabetic patient, a loading dose probably is not needed. You start with a low dose and you hydrate slowly, weekly or twice weekly, depending on the response to the insulin. I think the loading dose gets important when you switch someone from other basal insulins, because if you wait weeks before you're in steady state, that would give too much risk of hyperglycemia in that time. Yeah, and the only thing I wanna add is, I noticed in Thomas's slide, which I'm sure many of you saw, that Acadec profile on day two and day three and a little bit of day four, there was a significant difference there in contrast to day one and day four and day five. And Thomas mentioned briefly there that we would be potentially concerned in an insulin deficient patient, like especially folks with type 1 diabetes, who are more likely to have increased glycemic variability, that on day two and day three, they're gonna potentially have a different expectation around their basal insulin. Do they need to do something different with their bolus insulin on day two and three, given the profile, which is difficult to do? What happens if I'm going out for a run on day two? Now do I have to make my run on day five rather, because I'm more likely to have hyperglycemia? So I think, I'm not in the FDA panel, but just reacting to this myself. I think you can see that the FDA is not looking at this from a type 1 or a type 2 perspective, because we all know how easy it is to misdiagnose and confuse the two diagnoses. And so they're looking at it as this insulin molecule, are we making this insulin available? And we know that even though these may be type 2 patients, they may be actually misdiagnosed as T1 or vice versa. So it's a tricky situation. And that's, I think, why the committee this week, the advisory board has raised concerns. And we may have some more discussion a little bit later about that, but something to kind of address up front. Yeah, on the other hand, I mean, you will see the data when EDA presents the clinical trials. It works really, really well in type 2 diabetes. So the concerns around type 1 are worth mentioning, but I think the main population for once weekly insulin would be a type 2 diabetic population. Yeah, with that. All right. I'm heading over to you. Eda, please show us the innovations. We have new glucose lowering agents, so many of them very effective. But despite that, 20 to 25% of our patients with type 2 diabetes still require insulin treatment. So insulin is still lifeline for many of our patients with type 2. And the harsh truth is that many of our patients with type 1, type 2 diabetes are not achieving glycemic targets. An analysis from 2010 showed that it was only 57% of patients with type 2, you know, were achieving A1C target less than seven. Thomas showed in other statistics, it's significantly lower. And then there was a recent one which showed only 45 to 50% of our patients are achieving glycemic targets. So those percentages are not going in the right direction. So it's imperative that we have innovative tools, new generation insulins to improve management of diabetes, to improve glycemic control, and for an ultimate goal of reducing complications of diabetes. So how can we improve diabetes with new insulin treatments? I think it's fair to define what is an ideal insulin before we go there, before we start talking about new insulins. An ideal insulin, basal insulin, should improve glycemia to reach glycemic targets. We don't want pronounced peak action. Now, this graph here shows insulin from insulin release from a healthy beta cell. For our meals, we want those nice peaks to keep the blood sugar in range. But when it comes to basal insulin, mother nature created the best system. And you can see, we don't, like you don't need a lot of peaks, peak insulin action, especially unpredictable peak insulin action for basal insulins. Again, less unpredictability is ideal. We don't want any guessing games when it comes to insulin action. Is it gonna be, is your glucose lowering action for that insulin gonna be different across your patients? How about day-to-day variability? What happens if you inject it at different sites? So again, no guessing game is needed for an ideal insulin, ideal insulin, whether it's basal or bolus, actually. We want low risk of hypoglycemia, especially for our patients with type two diabetes. We don't want significant weight gain. And people with diabetes face many challenges every day. You all know, it's not an easy disease. And treatment adherence and persistence is quite challenging for all of our patients. It could be described, it could be described as a burden. Even for us clinicians, there was a study that showed two third of physicians actually described injections as a burden to diabetes treatment. So what can we do to improve treatment adherence and persistence, which will translate into improving glycemic control? Well, maybe fewer injections. You know, nobody likes too many injections. So how do we achieve fewer injections by ultra long acting insulins, especially for basal insulins? That's why there was a significant momentum in this field. And we're trying to address treatment adherence and persistence. We know that 70 to 87% of our patients with diabetes are missing basal insulin dose injections. They're not compliant with their treatment. Three to four missed doses of basal insulin significantly impact glucose control. How about missed time insulin? If they're not injecting it on time, if they're injecting it late, that's a major issue too. And five to six missed time basal doses also impact glycemic control in an unfavorable way. So again, this brings us to ultra long acting insulins. And once weekly insulins could provide unique opportunity to simplify basal insulin therapy, to allow good glycemic control and ease burden of our patients. And maybe, you know, also reduce mistakes, medication errors too. I have so many people, their parents are an insulin injection. Every morning before they go to work, they go to their parents' house and do those insulin injections daily because their parents can't do it. So, you know, if you look at the patient center, if you look at this from a patient centered angle, this might, those ultra long acting insulins once weekly insulins could be a major game changer for those families, for people with diabetes and their caregivers too. Thomas already reviewed pharmacokinetic, pharmacodynamic data of once weekly insulins. And I'm gonna try to summarize the evidence for once weekly insulins. What are the outcomes and are these once weekly insulins delivering what they promise? So we'll quickly review eight clinical trials for ICODEC once weekly insulin. Onwards trial program is one of them. We'll also talk a little bit about some phase two. F-Citora once weekly insulin, we have four clinical trials, Q and trial program and some phase two studies. And then ICODEC semaglutide combination, four clinical trials, mostly combined clinical trial program. Now let's start with onwards trial program and let's dive into some data. This slide summarizes, this table summarizes onwards trials, just main features of it. We have onwards one through six. Six was for type one diabetes. So I'm not gonna focus on that at all. We're gonna focus on onwards trials one through five. These trials were designed to demonstrate the effect efficacy and safety of ICODEC once weekly insulin compared to other basal insulins. Comparators were insulin clargene, Degladec. And some of them, some of the subjects were insulin naive and some of the subjects were already on insulin. So if you take a look onwards one and three and five, those were insulin naive subjects and comparators were for onwards one, it was clargene, two, three and four, it was insulin Degladec. And for five, it was insulin clargene, either U-100, U-300 or Degladec. And for four, some of them, those patients were also on as part insulin injections too. So this is the main kind of like a summary of these trials. I think one interesting thing here is like, how do you decide, how do you initiate a once weekly insulin? Because we clinicians, we all know how to change the insulin dose or determine the basal insulin dose for daily insulins, but how do you do it when it's once weekly? So here's how they did it during those trials. First of one unit of ICODEC has a comparable glucose lowering effect to one unit of comparator basal insulin. So at randomization, the once weekly dose of ICODEC corresponds to seven times the once daily dose of basal insulin. And for insulin naive patients, they started with 70 units of ICODEC and then titrated every week. And if you are on basal insulin already, they give a 50% additional loading dose, which equates to, instead of seven times the basal dose, now you're multiplying the daily basal dose with 10.5. And then they titrated weekly depending on fasting blood glucose levels plus or minus 20 units for ICODEC. And you can see the little table there. Their goal was, especially in ONWARDS-2, target blood glucose was 80 to 130 milligram per deciliter, which is the ADA target. So drum rolls, what happened? What were the outcomes of the study? Well, ONWARDS trials, ICODEC reached a non-inferiority. So they reached a primary outcome. You can see, for all of them, you see our check marks, the order is off ONWARDS-1, 3, 5, 2, 4, confirmed non-inferiority. And then the other important thing was, look at the hypoglycemia rate. So clinically significant hypoglycemia, severe hypoglycemia, these rates were not increased with ICODEC use. And for some studies, for some of the trials, ICODEC actually was superior. So let's take a look at the next slide. This one is from a review study, and you can see on the top panel, each ONWARDS trial, the order is, you know, this time it's 1, 2, 3, 4, 5. So for ONWARDS trials 1, 2, 3, and 5, change from baseline A1c was statistically significant for superiority for ICODEC. So ICODEC actually did better during those trials. In time and range, most of you are familiar with those bars. you know, the green is time and range, the yellow is, you know, time above range, the red area here is time below range. During trials onwards one, two, and four, insulin iCodec showed a trend in greater time and range, you know, for those specific trials. So time and range was either, you know, same when you look at iCodec outcomes and compare it to the basal insulin or, you know, sometimes slightly better. So this slide shows a meta-analysis and during this meta-analysis, they actually pulled phase two data for iCodec and phase three data and weekly insulin iCodec compared with daily insulin analog showed a higher reduction in A1c. Another important thing was greater proportion of subjects reached target A1c levels below 7% when they were on iCodec and there was, again, no increase in hypoglycemia. There was prolonged time in range with iCodec treatment and there was no statistically significant differences in frequency of clinically significant and severe hypoglycemic events. Now I want to draw your attention to this forest tape graph though. So this is your, you know, each line represents a study and this is your no effect line and look at the diamond. This little diamond represents their final study analysis for the meta-analysis and it shows the weight outcome and it favors long-acting insulin, meaning they found in this meta-analysis iCodec resulted in some weight gain. But then we have another meta-analysis and during this meta-analysis, they mostly focused on phase three trials. So we have our, you know, same diamond here, no effect line, and now we have onwards trials one through five, but this time our diamond is on this side favoring iCodec, meaning during this meta-analysis, they actually found that iCodec patients lost some weight and rest of the outcomes were pretty much similar in terms of reduction in A1c, time and range improvements in hypoglycemia. How about some other safety outcomes? Nothing impressive, injection site reactions and intrapatient variability. There was no significant, you know, variability. Another important thing was there was no significant variability. When you inject iCodec at different sites, thighs versus abdomen. Now let's switch gears and talk about F-Citora QWIN trial program. F-Citora weekly insulin, you know, there were five trials, but fifth one is type one. So we're not going to discuss that. One through four is going to be our focus. During this study, it was, you know, insulin-naive patients. Also some patients were already on insulin and their primary outcome measure was also reduction in A1c. Secondary outcome measures were mostly, you know, similar time and range, time above range, time below range, and hypoglycemia. So we don't have a lot of, you know, info regarding their data. They just did, you know, press release. But what we know is, you know, how like they tried different dosing titrations for F-Citora. I'm not going to get into details, but they used a similar loading dose at the beginning of the studies for F-Citora 2. And they've shown that loading dose strategy found to be safe and effective in reducing transient hyperglycemia for those subjects. And what were their outcomes? As I mentioned, we just have press release for two major trials, QIN2 and QIN4, and it was F-Citora versus daily insulin. And outcomes of these studies showed the reduction in A1c was similar for F-Citora and the basal insulin. So it proved non-inferiority for F-Citora. And hypoglycemia rates were also similar. There was no increase in hypoglycemia rates. We have some data from Phase 2 studies for F-Citora, a bit more detailed, and, you know, that actually aligned with what we've seen in those press release outcomes. In terms of A1c reduction, also non-inferiority was proved. In terms of fasting glucose values, both F-Citora groups and basal insulin, you know, fasting blood glucose dropped. Fasting blood glucose was slightly higher for F-Citora. But again, hypoglycemia rates, there was nothing significant in terms of hypoglycemia. And this slide shows time and range. Time and range, hyperglycemia, hypoglycemia was similar for all groups through 32 weeks for the F-Citora Phase 2 trial. How about if we quickly compare time and range for F-Citora and iCodec? You can see iCodec time and range. And this table, insulin naïve, insulin treated, and insulin naïve during the titration study. And right below that, it's F-Citora time and range percent. Again, insulin naïve and insulin treated. If you look at iCodec loading dose time and range, 72.9, non-loading dose 66. So time and range for iCodec was actually pretty good, comparable, you know, when you compare it to other basal insulins. But you can see with loading dose, iCodec achieved a higher time and range than those receiving, not receiving a loading dose. And for F-Citora, on average, the time and range was ranging between, you know, 60 percent to 76 percent for those patients. And F-Citora was well-tolerated for Phase 2 trial, well, for Phase 2 trials at least. And during Phase 2 trials, there was an imbalance in hypersensitivity reaction, 6 for F-Citora, 1 for Deglodec. But we'll see, you know, how Phase 3 trials will pan out once they release that data. And there was no variability for F-Citora as well. So it was low between day and between patient variability regarding—with regards to glucose lowering activity. Our final one is iCosema, iCodec Semaglutide Combined Trial Program. It's, you know, 1 through 4, and also, you know, some were insulin-naive, some were already on insulin. And we have a press release. We don't have the full data set for this study. And just to give you some highlights, A1c reduction was similar for iCodec Semaglutide group versus the daily insulin group. And there was—actually, in terms of hypoglycemia rate, iCodec Semaglutide did a better job with fewer hypoglycemic episodes. I think another important outcome was weight loss. With iCodec Semaglutide, there was 3.6-kilogram weight loss for the iCodec Semaglutide group, and the other group actually gained weight. They gained 3.2 kilograms. And common side effects were mostly what you expect from GLP analogs, mostly GI effects, but it wasn't to a level that there were severe GI effects. So what did we learn from these studies? What does the evidence show? Well, iCodec demonstrated superior glycemic control compared with daily insulins in four of the six trials, and in two of them, there was non-inferiority. And so iCodec showed a favorable safety profile. There was no increase in hypoglycemia and other side effects. There were no significant adverse side effects. There was no change in variability. Another thing that was reported from some of the trials was there were questionnaires about treatment satisfaction, and those were pretty, like, significantly greater for the iCodec group. Insulin F-sitora demonstrated non-inferior glycemic control compared with daily insulins and a favorable safety profile in phase two clinical trials. And the combined study, iCodec Semaglutide demonstrated non-inferiority glycemic control compared with daily insulins and superior reduced risk of hypoglycemia along with really favorable, I'm going to call it, weight benefit in the combined three phase three trial. So again, what's the take-home message? Well, we have evidence that, scientific evidence, indicating once weekly insulin work, they either achieve similar reduction A1c compared to basal insulins or even better reduction at times. We're achieving same time and range or sometimes slightly better time and range. And side effects, adverse events, are not high, and, you know, these insulins, once weekly insulins, offer a safe and effective option with a convenient dosing regimen, potentially reducing the burden of insulin therapy for people with type 2 diabetes. It can simplify treatment for our patients and for their families. Who are candidates for once weekly insulins? I've got a couple of thoughts. So maybe I'll start and answer the question to start off. So some of the people that I think about that could do really well in my practice are folks who, as we all know, are really struggling to be able to remember, take their insulin. Shift workers, I have a lot of people who just really struggle. And even Degladec and U300 Glycogen don't necessarily solve that problem. I know with an endocrinology audience here, I'm sure some of you have patients who take their levothyroxine once a week and, you know, they just, they need supervision. So I could see some of my patients who have got significant psychosomatic issues, people who are institutionalized that may have significant benefit. I know I have some of my patients who come to my clinic so that our nurse educators can actually inject their GLP-1 receptor agonists once a week. So I could see a real role for that in my practice. Those are a couple of things just on the top line that I can think of. Any other thoughts from you guys? Well, I think patients who are afraid of injections or are concerned about the burden of injections are definitely another group that is, would be very interested in a once weekly insulin. Ede, anything from your side? I agree. You pretty much said it all, but a lot of patients, I saw that big box, you know, the word art, you know, compliance. If anybody's having major compliance issues, needle phobias, and I mentioned it, you know, some providers are like some caregivers, they definitely, I know so many families that I have that they prefer once weekly insulins. And I think there are still so many things we need to find out about once weekly insulins, like what happens if you exercise, what happens at the hospital when they're admitted. Maybe it's a better option at the hospital, maybe not. But you know, again, there's so many potential patients that might benefit from it. I think the second question, how we ultimately adjust glycemic regimens when you switch to once weekly regimens, I think maybe just two sentences from each of you, what would you do if somebody was on glipizide, maybe, Ede, to you, and Thomas, if they're on semaglutide or trazapatide at a high dose, what would you do? Reduce the dose. I think when you have someone on insulin already, we have discussed it, the loading dose is very helpful. When you have one high dose of GLP-1, because of the co-effects you get on efficacy, you can reduce the GLP-1 dose. Similar answer. Similar answer. Yes. Let's keep moving along. What happens if a patient misses a dose? With the once weekly insulin, you just continue when you remember that you have forgotten your dose. And because of the long half-life, you have much better overlap of your profiles and it's less relevant. Perfect. That's good news. Okay. Let's get to the last bit here. And this is an interesting patient voice. So this is actually a real patient that was interviewed for this. And it's actually quite striking and something that I'm sure many of you have heard. And how I learned something was wrong is my husband and I were moving cross country. And that long drive, I had an unusual need to keep stopping to use the restroom. And then my feet started becoming numb. Once we got settled into our new home, I had blood work done. And that's how I found out I had diabetes. Shortly after, I fell and ended up being hospitalized when I split my lip open and received stitches and a prescription. My son took me to the pharmacy to fill a prescription for insulin, but I didn't have any instructions or any idea what to do. So we YouTubed what to do. When we watched the video, we realized we didn't have the needle and that that was sold separately. So we drove back to the pharmacy, which is a 30 minute drive to get to, just so that I could take my first dose of insulin. Really, everything I've learned about my insulin has been from Dr. Google. I'm in rural North Carolina, so my resources are limited. I've just used the internet to try to get more informed about my diabetes and insulin. There has to be a better way. I'm sure many of you have heard that. And so this slide really just summarizes what many of us know, as that insulin, it's not a prescription that we necessarily just send to the pharmacy and say, well, if you go and go and figure it out, there's multiple, multiple steps. And in the context of this conversation, there's less steps for a patient on a once weekly insulin. That's a fundamental take home point. We know that we have to teach patients how to use glucagon. That's part of the process. We teach our fellows that all the time. Somebody doesn't leave the office unless they know how to actually manage hyperglycemia that comes from insulin. We're also aware of this concern around hyperglycemia. So we also, we tend to go slow with insulin. We tend to start slowly. We don't want them to walk out and lose confidence in the first time they ever take an insulin injection and have a hyperglycemic event in the first day. We know that that impacts our relationship with the patient and their confidence moving forward. So when we think about this, and I'm obviously framing everything for you guys, think about this into the future when these insulins become available, how do we use these insulins and think about these insulins in the same way that we think about the insulins that we use today and how we educate and prepare patients for insulin use. We know this insulin is not a threat. Many of our patients see this as this very big needle. And here we're giving this very small needle less frequently. And there's power to that, obviously. This is another statement that I'm sure many of you have heard. Drugs don't work in patients who don't take them. And it's very, very self-explanatory, but I love to put it up because this is a potential opportunity here for us to improve this. So we've already gone through this data, and this is just a reiteration of the slide. Our patients struggle. I don't like the word compliance. I'm sure many of you don't like it either. Even the word adherence is a kind of nasty word sometimes depending on how you think about it. But we know that we have a responsibility as healthcare providers to help our patients adhere and persist to therapies that we give them that they're going to be taking for the rest of their life in many of our cases. And I think this is a great opportunity for us to move the needle forward here. So this is the word compliance that I just mentioned that we don't like. Brian says, I don't really like that word either. We agree with him. It's not like you're refusing the doctor's advice. You're just making the wrong decisions. We're asking our patients to make decisions every day when we're asking them to take basal insulin. What do they do when they have the colonoscopy? What do they do when they're planning to go for a run? What do they do? We're constantly having to ask patients more and more and more when they're doing these therapeutics. So we know we have to have shared decision-making with our patients. And we know that potentially these insulins are going to help us with the shared decision-making process. I think about Akosema in terms of the weight loss that's presented here is a really powerful conversation that I can use with my patients in the future. We're already asking them what time of day potentially they're going to inject their insulin. What's an appropriate time for them? Now we're asking them when can they do this once a week potentially? Can I give them greater choices? I think that's what's really exciting about this field is that as insulins move forward, as Thomas mentioned, from the days of MPH, we now have so many more choices for our patients, which is really exciting. And we have an opportunity to discuss what their preferences are going to be. What do you think? Does MedliDoc best for you? What about MPH? Is MPH still an option for some of our patients? Is it still on the table? Shared decision-making, this gives us greater opportunity there. And so we know about the disease. Many of us know a whole bunch more than our patients will ever know. We know the tests. We know the treatments. But the patients know what their expectations are for their own body, their lived experience, their circumstance, and what their goals are. And how do we align our insulin therapeutics and whatever other therapeutics we have with the patient's expectation and how that aligns with what we know? And that's what this is all about, really. This is just an interesting survey that I want to just go through, and it may not be surprising to most of us, but actually I was really surprised by the numbers. So this was published recently in February of this year. David Kerr and a group did a survey that they sent out to endocrinologists and patients, and it was about 400 in each group, asking them what their preferences would be if they lived in a hypothetical world where these once-weekly insulins were available. And you can see that 91% of patients and 89% of—it wasn't just endocrinologists, it was diabetes clinicians. There were some primary care docs involved and other diabetes clinicians. And you can see that the vast majority in a hypothetical world would choose once-weekly insulin without even knowing about it. And so that's pretty striking, and maybe the numbers are higher than I would have thought. And they also asked them on a Likert scale, a typical one-to-seven Likert scale, those that were already using insulin, would they feel more confident that using once-weekly basal insulin would help them to achieve their goals? And more of them agreed, which is interesting to me why they would have thought that, but more of them did. And there wasn't necessarily a difference whether they were insulin-experienced or not. So the numbers were pretty impressively high. So I think our patients are excited and looking forward to this opportunity to be able to use these therapeutics. So this patient said, I'll worry about any once-weekly medication. This is the flip side. What happens if you have a bad reaction? Now you're stuck with it for a week. I think many of us had to address that when the GLP-1s, the once-weekly GLP-1s, came out. What happens? It actually wasn't potentially as bad for many of us as what we thought it was going to be. But this is another guy, Ron, who says, how big is the shot? Wow, imagine I need 100 units a day, now I'm going to be taking 700 units? How much insulin is that? Maybe you're going to look like you've got a golf ball under your skin. And maybe that's something we'll have an opportunity to discuss that we haven't. Is this really the case that they're going to need this much insulin under their skin? So these are the questions we're going to have to address with our patients. Also what happens when you have hypoglycemia? Am I going to be hypoglycemic for the whole week? And this is a study that Thomas did, so I'm going to let him speak over this because he's the expert on this and this is his work, and he'll address that question. The question we wanted to answer was, what happens if you give accidentally a double or a triple dose of your insulin, and we compared that to the GARGIN U100, give a double or triple dose, or Icodec double and triple dose, and we were looking into how fast hypoglycemia occur and how low patients did go, and there was no difference. So if a patient has hypoglycemia, even with this long-acting insulin, there's no longer duration of hypoglycemia and there's no repeated hypoglycemia. It's just one hypo, you defend that with carbohydrates and there you go. So there's no increased risk of prolonged hypoglycemia if patients are accidentally giving themselves a second injection. Despite all our advances and all of the really good insulins we have today, we have challenges still, and we now have the potential of new insulins that are coming down the pike that are pretty exciting, as well as the combination to connect them with GLP-1 receptor agonist therapy, which we all like and use. These insulins appear to be safe, particularly and effective in people with type 2 diabetes, and they offer a great opportunity for us to advance the needle, as we've already said a few times before.

once-weekly basal insulin

insulin ecotec

insulin f-citora

diabetes treatment

glycemic control

clinical trials

A1c levels

hypoglycemia

patient preferences

diabetes management