All right, we're gonna be discussing today expert updates on the latest advances in the development of weekly insulin formulations. A very novel and innovative topic, so we really want to get feedback from you. I'm Rodolfo Galindo, I'm an associate professor of medicine at the University of Miami. Before that, last year I was at Emory University for a few years, and then just recently moved there. And then I have with me two great colleagues, Professor Dr. Juan Frias, who is a medical director and principal investigator in Velocity Clinical Research Center in Los Angeles, and our Professor Carol Wieschan, she is the past president of the Endocrine Society. Thank you so much for your service, it's a dedication, and thank you so much for accepting to be part of this program. So I'm very excited because we have a lot of experience from both of them here. So these are our disclosures, you have them also available. And then we're gonna just go over the learning objective. So our session today is gonna be focusing on these new formulations. We're gonna try to identify challenges with daily basal insulin that may be overcome by weekly insulin formulation that are in development. We also want to compare the mechanism of action, the efficacy and safety of the weekly insulin formulations that are in development, and compare that with daily basal insulin. And then at the end, we're gonna try to evaluate some strategies to address patient and provider barriers to implementing weekly insulin use into clinical practice. So the latest section is what is really gonna be very interesting because we want to get feedback from all of you. So now I want to welcome our past president of the Endocrine Society, Dr. Carol Weishen. She's a clinical professor of medicine at the University of Washington, and an endocrinologist at the Rockwood Center for Diabetes and Endocrinology in Washington. Thank you so much, Carol, for being here with us. Thank you. Thank you. Thank you, Rodolfo. I have the pleasure of reviewing some of the challenges that we have in using basal insulin in our current practices, and just want to note, if it's not already clear, we're really gonna be focusing on type 2 diabetes tonight because that's where we have the most data as it relates to these once-weekly insulins. So I know that you've seen a similar slide many times in the past about the natural history and progression of type 2 diabetes. And of course, we know that insulin resistance goes up, but that glucose levels don't start rising until the insulin level starts to drop, and that is related to the reduction in both beta cell function, as well as ancretin function. As the insulin secretion goes up, they develop prediabetes, and then once type 2 diabetes occurs, we generally start with metformin, and then progress on in a stepwise fashion with injectables and then insulin therapy. So according to the latest ADA recommendations for how to start insulin, it's important to remember that if you have a patient who has severe hyperglycemia, particularly those where they have symptoms of hyperglycemia or when you suspect type 1 diabetes, you should start insulin immediately. However, if you have a patient who has marched through the oral medications, if they're getting ready for an injectable, a GLP-1 receptor agonist should be the first of the injectables. And then if the patients need additional glucose lowering effect, it makes sense to start basal insulin using either 10 units or using 0.1 to 0.2 units per kilogram per day. They generally recommend bedtime, although flexibility should be considered, and in fact, data suggests that patients do a bit better if you give their basal insulin once daily in the morning as opposed to the evening. Titration should occur to target and patients should be educated to do that. And then of course, if you need to intensify, you would intensify with any medication, perhaps if they're not already on SGLT2, go ahead and start that. Or you can use basal plus MDI, pre-mixed insulin, or even insulin pump therapy. So our basal insulins as of this point in 2023 include NPH insulin, which we still will consider a basal insulin. Its issue is due to the high variability, the highest risk for hypoglycemia, and very little flexibility in terms of dosing. Many patients need twice daily dosing to get optimal control of their basal insulin. Similarly, insulin detomer has a relatively shorter duration of action, particularly in some individual. It's intermediate in terms of variability and hypoglycemia, as well as dosing flexibility. But at least a third of our patients on detomer also need twice daily dosing, which is a definite disadvantage. Insulin glargine, again, has a variable duration of action in different patients, as well as a different variable action of insulin with patients on very high doses of insulin. So it too often requires split dosing if you get much more than the 50 units or 0.5 units per kilo. Insulin glargine, U300, greater than 24 hours, least variability, lowest hypoglycemia, and does have better flexibility for timing. And then insulin degladex, the longest duration that's currently on the market, least variability, again, low hypoglycemia. And the most flexibility. So if we look back and we look over the course of the last 25 years or so, we can see that for patients whose A1C's targets are less than seven, that we have actually had a deterioration in the percent of patients who've reached target from a peak of 57.4 in 2010, down to 50.5 in the 2018 NHANES database. Less than 8%, the numbers do continue to go up slightly, but that still leaves about 25% of our patients who are in very poor control, as defined by an A1C over 8%. During this same timeframe, you can see on the right-hand side the types of medications that are being used in the United States, with the green being any medication and the metformin being the blue, and you can see a steady increase in the amount of metformin being used, which is very appropriate. You can see the sulfonylurea has decreased such that now over the course of the last 25 years, it's gone down by about 15%. Insulin has gone up to about 25, 26%. You can see that as of 2018, there's very poor penetration of the SGLT2 inhibitors or the GLP-1 receptor agonist, as represented by that light lavender color. So, not in the same timeframe, but looking at the last data that I could find, so in the United States, in patients with type 2 diabetes, about 57% at that time were on orals, and again, very slow, low penetration of GLP-1, so those aren't really in that graph. 14% were on no meds, 29% were on insulin. Now, I don't know what the right number is. How many, what percent of patients with type 2 diabetes should be on insulin? But what I can tell you is probably, at least at that time, should have been more because if you look at those patients on insulin, 38% of them had an A1C that was at or greater than 8%, suggesting that they have not been adequately controlled with the basal insulin that's being prescribed, and about 34% were less than 7%, and we see this all the time. The control in insulin-treated diabetes is significantly worse than those that are treated with other agents. Part of the problem, and this has been shown over and over, is that in most countries, including the United States, that patients' A1Cs are considerably higher than 7%, considerably higher than 8%, and in some case, 10% on average before insulin is even started, and there is absolutely no way that you're gonna get a patient who starts with an A1C of 10%, and with added insulin alone, you're gonna get their A1C less than 7%. So the higher the A1C when you start, the more likely you're going to need to be talking about a more intensive regimen than just basal insulin. But nonetheless, one of the very telling things in this particular study is that the lowest A1C was reached at six months after beginning therapy, and that despite an additional 18 months of treatment, during which time the insulin should have been titrated, there was no further improvement in the A1C. So you've all seen, again, something similar to this, and I just wanna build up to the time we're talking about adding insulin, and in this database done in the UK, it was an average of six to 7.1 years between adding the third oral med and adding insulin, and then another 3.7 years before the insulin therapy was intensified. So you can see that if you add up all of those years together, the average patient in this database, you're talking about somewhere around 15 years of hyperglycemia of glucose levels above target prior to getting fully intensified on their regimen. And again, this is another way of looking at that, and that is waiting until somebody's A1C is quite high before you go to the next level, which is what's been shown in many of the studies. And the recommendations of what you could do is that if you started initial combination therapy and you up titrated the patient as soon as their A1C reached above seven, and the difference in the area under the curve for the amount of exposure to hyperglycemia over time is dramatically different with the second protocol versus the first. And this has been codified in the new ADA algorithm. They've really impressed upon the importance of really addressing A1C very aggressively from the beginning, either using combination therapy or using a powerful GLP-1 receptor agonist shortly after or upon diagnosis of diabetes. So other data that have been done which demonstrate the magnitude, again, of the persistence of poor control. Another study, average A1C around nine and a half. They were started on insulin, titrated, and followed. And you can see the percentage of patients whose A1Cs were above nine decreased substantially from 45% down to about 15%. So those patients in very poor control did quite a bit better. But none of the other groups increased or changed significantly. And generally, probably what was happening is each group was just going from the higher group down to the next step down as opposed to coming down into the 7% range. And once again, you look at whether you count that as six months or nine months, that's when the lowest A1C was achieved and no further adjustment or improvement in A1C over a seven-year period of time. So we know that patients and physicians are reluctant to start and initiate and advance insulin. We have the healthcare professional issues and we have patient issues. Starting with the patient issues, much of that is related to what we talked about earlier as far as being too busy, the impact on the social life, not wanting to take your insulin with them to go have dinner. Many of them, because they're not titrating, they're not seeing their blood sugars get better and therefore they don't think it works. They aren't given the confidence and activated to titrate their dose. They frequently forget doses and we'll talk a little bit about that. They're also concerned about weight gain and some of the negative things they've heard about insulin. Whereas in practice, the healthcare professionals have time constraints. They don't know and aren't comfortable activating their patients to titrate and they don't have support and resources for helping to help patients get over their barriers. And again, the patients will report lack of time, lack of flexibility and embarrassment. So diabetes education, starting from the beginning to address misconceptions as insulin being replacing what's missing, less burdensome regimens, using a nurse or pharmacist-led management and then using titration apps. Titration is abysmal, whether you're talking about overall the US, UK, other countries, you can see that within approximately 27 months that the average titration overall was only 10 units. And that might be explained by doing two units every three months for the course of 27 months. And again, non-adherence with insulin is common. At least 33% report missing or admitting insulin at least once a month. It's common for me to determine and count up that patients are missing their insulin with MDI 14 or more times per week. And again, if you ask the survey, they say that number one reason is that they're too busy. The last reason, the lowest reason, only 2.6% said they were worried or they weren't taking it because the injections were too painful, which of course is what many physicians believe. So improve adherence to insulin. Again, important to use diabetes education as it has been shown to improve treatment adherence, improve patients achieving targets, and increasing insulin use to lower chronic complications. Well, what about the use of a once-weekly medicine? Now, obviously we have no real-world data with once-weekly insulins because they aren't available yet. But the best I could come up with was a study that was done looking at adherence, persistence, and glucose lowering effects of once-daily versus once-weekly GLP-1s. And these were propensity match score from a large insurance database. They had balanced cohorts of almost 800 patients in each cohort. And if you look under adherence, you can see it's still abysmal. In the once-weekly, it was only 54% were adherence with their therapy, but it was substantially higher, about 23% higher than in the once-daily. And at 12 months, similar statistics occur. And then if you look at blood glucose levels by mean A1c, you can see that there was a significant difference in A1c lowering at six months, but it did not persist to 12 months. So again, we still have these barriers, and once-weekly may help with some of the impact on social life and the lack of time and forgetting. But there could be other technology that we could use to help deal with the remaining barriers. And one of those has to do with an automated versus conventional basal titration advice. And these are meta-analysis of several studies, first with insulin-naive patients on the top, a patient of mixed insulin-naive and pretreated on the bottom. And what you can see at the very bottom, that there was an overall improvement in A1c of 0.25% with the automated versus the basal insulin titration advice. And these were very early studies with very primitive automated advice and with newer apps and AI, I am sure we could do even better. So, why would we consider using a once-weekly basal insulin? Well, the initiation of insulin is still often delayed, and maybe a once-weekly option would be more palatable for the patients. The clinical inertia related to the patient as well as the healthcare professional. Basal insulin is suboptimally implemented and titrated. Maybe some concerns about hypoglycemia and weight gain, fear of injections, poor treatment adherence, and poor treatment persistence. So with this, I'd like to turn the podium over to Juan, to Dr. Frias, to take us through the data that we have currently with once-weekly insulin formulation. All right, well thank you, Carol, for setting the stage so nicely. It's nice to be here, everyone, and pretty amazing when we're putting these things together. I come from an era, I graduated from med school in 89, and that's when Matt Riddle wrote that paper about BIDS therapy, bedtime insulin, daytime sulfonylurea, and so that was like cutting-edge diabetes in my day, was adding MPH insulin to glyburide. So we've definitely come a long way, and what I'll be talking about is some of the once-weekly insulins, describing them and also providing some of the data that we have available. So there are two once-weekly insulins that are in clinical development. On the left, we have, and I'll refer to this sometimes as BIF, Basal Insulin FC, you'll see that on some of the slides, but more recently, the nomenclature is Insulin F-Sitora Alpha, or F-Sitora. And this is the fusion protein of a variant, a single-chain variant of insulin that is fused to the FC domain of an IgG. So this is the same sort of technology that's used, for example, by doulaglutide to extend its half-life, and it's used in many medications to extend half-lives. I'm gonna go through two phase two trials that were recently published, and this compound is actually in phase three right now, a program called the QUINT program. And the second once-weekly insulin is Insulin Icodec, and this is a basal insulin analog, and it uses, or the methodology it uses for extension of the half-life is being, having a 20-carbon fatty diacid moiety attached, which reversibly binds to albumin. So we know this from Insulin Deglodec, from loraglutide, from semaglutide, from terzapatide, and many other drugs that use this methodology to enhance the half-life and prolong the activity of the drug. This is Novo Nordisk's medication or drug, and it has completed its pivotal phase three, or phase 3A program, which are the ONWARDS trials, and we'll talk a little bit about those as well. Two of the trials, actually ONWARDS 2 and 4, were recently published. So this is Epsitora Alpha, you see the graphic there, so that's the FC domain of an IgG2, and you see it's a homodimer, so there are two single variant chains of insulin attached to it. It's a very large molecule, 64 kilodaltons, and it has a half-life of 17 days. Insulin Icodex half-life is about eight days, and we'll get to that a little bit later, and several mechanisms by which the half-life is prolonged. Just the sheer size, there's slowing of absorption from the subcutaneous space, there's neonatal FC recycling, or receptor recycling, this is true of albumin-bound molecules as well, reduced renal clearance, and importantly, there's reduced insulin receptor affinity. It is a full agonist of the insulin receptor, but there's reduced affinity to the insulin receptor, and this reduces endocytosis, or receptor-mediated endocytosis, and clearance, and this is true of insulin Icodex as well. It has low mitogenicity potential, and low immunogenicity risk. So what you see on the left are data from a single ascending dose study, so single doses, this is in patients with type 2 diabetes. This is out to 28 days, so looking at insulin concentrations after a single dose, three different doses, and what you see here is that the pharmacokinetics are dose proportional, with very low between-day and between-subject variability. What's seen on your left is a multiple ascending dose study, also in patients with type 2 diabetes, and this looks after the final dose in this study, so this is week six, and you see on the x-axis, this is after the dose, the seven days of insulin depository alpha concentrations after the dose is given, and the importance here is that it's got an extremely flat profile, so the peak to trough ratio has been estimated to be 1.14, and just to put that into context a bit, and I think, Belinda, you have a slide on this, comparing this to the daily variability we see with insulin glargine, and the daily variability with insulin glargine, as far as the peak to trough ratio, is about 1.8. With weekly insulins, we look at the peak to trough ratio across the full week, so very flat, and flatter than once daily basal insulins, and what you see on your left here is the pharmacodynamics of the glucose lowering in the single ascending dose study, basically over seven days after administration, so a dose-dependent reduction in glucose. You see the nadir. This is not at steady state, obviously. You expect it to be flat at steady state, but you see the nadir at about four to six days, which is basically consistent with once-weekly dosing, so as I mentioned, there are two trials, phase two trials that have recently been published. This was published in Lancet Diabetes and Endocrinology just a few months ago, and this was a study in patients already using basal insulin, so the mean age was 60, duration of diabetes, 16 years, A1CA.1, and their basal insulin dose at randomization was around 40 units, and importantly, about 30% of these patients were treated with sulfonylureas. You'll see in some of the other studies either sulfonylureas were not allowed or they were discontinued when the insulins were initiated, and basically here, there were two BIF or Epsitora arms with different fasting glucose targets, one, the target was less than 140 milligrams per deciliter, the second one you see there, less than 120 milligrams per deciliter. We also made the dose escalations. The insulin was given once a week, but in the first, the 140 target, the insulin dose was changed every two weeks, whereas with the 120, it was every four weeks, and then we compared to insulin deglodec given once daily, and the target for that was less than 100 milligrams per deciliter, and the reason these targets were different was because this is the first time this insulin had been used outside of a clinical research center where patients were basically hospitalized, so the first outpatient study. The dose adjustments were made based on fasting glucose, and at this point, there was not a unit to milligram equivalent, so we dosed in milligrams, and this was lyophilized powder that was actually reconstituted in the clinic, and the patients came in every week for their injection. It's a 32-week study, and the primary endpoint was the change from baseline in A1c, and you can see from a baseline A1c of 8.1%, similar change in A1c over the 32 weeks with insulin deglodec and with the two F-sitora arms, and in fact, between the two F-sitora arms, the A1c was similar. This looks at fasting glucose. As you would expect, because the fasting glucose targets were different, the F-sitora arms had higher fasting glucose, which you see in the hashed lines are the targets for the two F-sitora arms, so less than 140, less than 120, and then the target for insulin deglodec, less than 100, so despite the fact that there was similar A1c reduction, actually had higher, as expected based on the target, higher fasting glucose, and this could, you could think, theoretically be improvement in postprandial glucose, could be due to the longer half-life as well and the stability of the molecule. We did continuous glucose monitoring as well. This is shown between the three arms, again deglodec and the two F-sitora arms, similar time in range, time above range, and you can see the time below range, numerically slightly lower when looking at the CGM, and within day glucose variability here, daytime, nighttime, and over 24 hours, lower variability is measured by the coefficient of variance with the two F-sitora arms compared to insulin deglodec, and then looking specifically at hypoglycemia, in this trial, we actually saw lower rates and incidence of hypoglycemia, so you could see nocturnal, non-nocturnal, and throughout the day, less than 70, and also level two, less than 54 milligrams per deciliter. Now again, this could be due to the flatter profile, the decreased variability, but we need to take into consideration that the fasting glucose targets were different with insulin deglodec, 100, and the two F-sitora arms either less than 120 or less than 140, but definitely a trend towards less hypoglycemia, and then there were two episodes of severe hypoglycemia in patients in one of the F-sitora arms, both of these patients were treated with oral carbohydrates, recovered, and continued in the study, and very low with respect to anti-drug antibodies. So the second study, so that was a study in patients already on basal insulin. I will mention too, because we'll be talking about this, when these patients were dosed, their initial dose, there was a 1.5 to threefold increase, so a loading dose, and this is based on the fact that the half-lives are so long that to get to steady state more quickly, you'll see that in many of these trials, particularly in trials where patients are on basal insulin already, and we're switching them over to the once-weekly insulin, they will require a loading dose to more quickly gain control. So this is the second of the two type two diabetes, phase two trials of F-sitora, this was published in Diabetes Care earlier this year, and this was in patients who were all on meformin with or without an SGLT2 inhibitor, and or a DPP4 inhibitor, and this actually had similar targets between F-sitora, which was dosed weekly, and this trial had a threefold, when we calculated what dose we were gonna start them on, there was a threefold loading dose for the first dose, and compared to insulin deglidec, and in this case, both of the insulins, or both arms of the study, had similar targets, so less than 100 milligrams per deciliter, and the patients underwent blinded continuous glucose monitoring at baseline before week 12, and before week 26. The primary endpoint was a change in hemoglobin A1c, which is shown here, and they're basically superimposed, I mean, a very nice reduction, you notice in both arms here, the A1c, the mean A1c was less than 7%, you can see in the final bullet there, the proportion of patients achieving an A1c of less than 7%, 62% with F-sitora, and with insulin deglidec, which is in parity here, 69%. This shows the fasting glucose change, as expected, because they were targeting the same fasting glucose, and then looking at continuous glucose monitoring, so on your far left, the time in range went from about 65 to over 75 in both arms, again, similar control, if we look time above range, as you would expect, it went down, time below range went up slightly, but was higher with insulin deglidec, numerically anyway, compared to F-sitora, and slightly higher also, level two, or less than 54 milligrams per deciliter. Importantly, despite the fact that these patients on average attained A1c's less than 7%, there was no severe hypoglycemia throughout the study in either arm of the study. There were no serious adverse events related to study drug, no significant difference in treatment emergent injection site reactions, and there was some weight gain, which was comparable between the two arms of the study, F-sitora and insulin deglidec. So those are the two phase two studies. Basically, at the end of the day, whether it was switching patients from basal insulin to F-sitora, or F-sitora as the first insulin in insulin-naive patients, very good reductions in A1c, which were similar, and in the switch study, there was less hypoglycemia, but again, lower fasting targets, and in the insulin-naive study, there was similar hypoglycemia in that trial, numerically slightly lower. And this shows the QUINT program, basically. So it's a program across both type two and type one diabetes, looking at patients that are insulin-naive, so F-sitora as the first insulin in these patients, either versus insulin glargine, or insulin deglidec, or switching patients who are already on basal insulin, and a study as well in patients who are on multiple daily injections, on basal bolus compared to insulin glargine. We won't get into QUINT-5, but that's a trial that's initiated, in fact, all these studies have initiated in patients with type one diabetes versus insulin deglidec. Just briefly, the timelines here. In the bottom line, the last study to finish will be QUINT-1, and that'll be sometime in 2024, so I would expect probably some regulatory action in 24. So these insulins are coming relatively soon. So iQEDEC now. So iQEDEC, as I mentioned before, has actually finished its registration trials. In fact, it's being reviewed currently by FDA, so we have a little more data here. This shows the molecule again. So there are three amino acid substitutions. It's an insulin analog, and this reduces enzymatic degradation. It lowers insulin receptor binding affinity, as with Epsitora, slowing insulin receptor mediated clearance, and it improves solubility. So the formulation is a U700 with respect to the concentration, because these are obviously very large doses, seven times the doses that you would give once daily. And then with the fatty acid moiety, as with many other drugs, so this is reversible binding to albumin, and it has the effect of prolonging the half-life. This is a multiple ascending dose study. This is towards the end of the study, so week five, looking here at pharmacokinetics. So this is looking at insulin iQEDEC concentrations. Over 168 hours, and I had to divide that by 24 to figure out that that's seven days. So this is like how many days, but you see dose proportionality. You see a mean half-life of 196 hours, which is around eight days. Again, Epsitora is about 17 days, and a Tmax at about 16 hours, you can see there. And actually, during the study also, it was very interesting, towards the final week of the study, clamps were performed at day two and seven during the one-week period, and what these bars represent is the proportion of insulin activity, or the glucose infusion rate, of the whole activity of seven days. So if you looked at this, across 100% divided by seven will be like 14 point something or other percent. You can see it's actually quite similar, the glucose-lowering activity across the seven days, but you do see a slight increase, so like 13% of the week's glucose-lowering activity occurs in day one, about 12% in day seven, and you can see about 16% through this modeling in day three. So pretty flat as well, but clearly not completely flat. I'm not gonna go into great detail in the phase two studies. There were three really nice phase two studies that were published. The first one was in the New England Journal, this is Julio Rosenstock's paper, and two of these were in patients where the insulin was their first time, so they were insulin-naive, basically. Julio's study was a 26-week study, and I'll just say things that are sort of relevant to the phase three trials. In this study, patients were on oral agents that were started either on 70 units of Eicodec, if you divide 70 by seven, that's 10 units a day, or 10 units of insulin glargine. All of these studies compared to insulin glargine, and got exceptionally good control. Everyone went down, both arms, I should say, into the sixes with respect to A1c, and similar A1c. Their target, though, was 70 to 108 milligrams per deciliter. The Eicodec was titrated once weekly, the insulin glargine also titrated once weekly, clearly given once daily, though. They did see a small increase in the rate and the incidence of level one hypoglycemia, maybe not statistically significant, but also an increase in level two hypoglycemia. And I think this played into the next study, which is in green there, which is Ildi Lingve's trial, which looked actually also at patients who had not received insulin before, so they were on oral agents, and actually looked at different targets, so 80 to 130, or 70 to 108, and also different titration doses, either 28 units once a week, or 21 units once a week. So basically, four or three units daily would be the equivalent. And what they found, long story short, is that really what gave the best balance between glycemic control and reducing the risk of hypoglycemia was a target of 80 to 130, and the increments were making the changes in insulin of 21. And this is very similar to what then moved forward in phase three, where the targets are, in all of the ONWARDS trials, are 80 to 130, and the adjustments are made in 20 unit increments once weekly, if needed. And then lastly, in the middle there was a trial in patients already on basal insulin, and what was assessed here is the necessity for a loading dose. So basically, there was an IQADEC arm where when the dose, the starting dose was calculated, they had a loading dose of two-fold what the calculated starting dose was. They had an arm with no loading dose, just basically taking the patient's previous basal insulin dose, the daily basal insulin, multiplying it by seven, and starting with that dose as IQADEC instead of double the dose, or an arm with insulin glargine. And basically what it found, and Galindo will be showing a slide on this as well, is that the loading dose really prevents this initial potential rise in glucose as you're getting to steady state with the once-weekly insulin. So what kind of came from all of this, if you look at the phase three trials that we'll talk about briefly now, is that in patients who are switching from basal insulin to a once-weekly, once-daily I should say, to a once-weekly, in the ONWARDS trial, the loading dose was 50% more. So it was a 1.5 multiple, if you will. And again, that's a one-time loading dose. The changes, as I mentioned before, are made in 20-unit increments, and the targets for fasting glucose are 80 to 130 milligrams per deciliter, and that was really based on all of these studies. So I've said all of that. For the sake of time, I won't repeat it. But this brings us to the ONWARDS program, and unlike the QUINT program, a very comprehensive program, and the top row are ONWARDS I, III, and V, which are trials in insulin-naive patients with type II diabetes versus insulin-glargine, insulin-deglutectin, and Carol, you'd mentioned a guidance app. I mean, ONWARDS V actually has a guidance app to help with titrations as well. On the bottom, you have the trials in patients who are already on basal insulin, ONWARDS II, ONWARDS IV is patients who are on basal bolus, and ONWARDS VI in type I diabetes. And basically these trials, two of these have actually been published, ONWARDS-2 and ONWARDS-4, and I've got a couple slides on those. But this shows, this comes from press releases and whatnot that has been disclosed publicly. And you can actually see that in, for example, ONWARDS-1 there, you see a significantly greater reduction in A1c compared to, I think that was, Dwarjean, thank you Carol. Glad Carol's here. In ONWARDS-2 as well, you get, and that's compared to Degladec, you have a reduction there. Also in 3 and 4 we'll be showing, and also in 5. So many of these trials, you have significantly greater reduction in A1c compared to insulin Dwarjean or insulin Degladec. And on the bottom you see the rates of clinically significant hypoglycemia. So in this case level 2, I think this includes level 3 as well. So maybe some slight increase to equivalence, but the bottom line is that except in the basal bolus trial, which is ONWARDS-4, very low rates. I mean less than, significantly less than one event per patient per year. And many of these trials without any severe hypoglycemia despite very good control. So ONWARDS-2 was a study in patients already on basal insulin. And they were switched then to ICUDEC versus insulin Degladec. The target for fasting glucose was 80 to 130 milligrams per deciliter. And this is the primary end point, the top left there. Significantly greater. This was a non-inferiority trial. They showed non-inferiority but also superiority with ICUDEC versus insulin Degladec with respect to A1c reduction. You can see A1c goal attainment. 40% of the patients treated with ICUDEC compared to 26% treated with insulin Degladec. And you see also the composite end point of attaining either less than seven or less than or equal to 6.5 without any clinically significant hypoglycemia. Higher also for ICUDEC compared to Degladec. And this shows continuous glucose monitoring that was conducted. This shows it actually was conducted in various points of the trial but at the end of the study here. And you can see as you would expect based on these A1c results, less time above range, slightly greater, numerically anyway, in range and quite similar with respect to time below range. This looks at the insulin dose which was quite similar. You can see in the dark blue line, you start, and this, you know, Galindo will talk about this a bit more. I mean, it's a bit scary when you're doing these trials and you're suddenly dosing someone close to 250 units of insulin. But that was the loading dose here. These patients were on about 26 units of insulin at baseline. So if you multiply that by seven and then multiply that by 1.5, you come up with this 240 something or other. And so that's that initial dose. But then you can see that throughout the trial anyway, the doses were equivalent. And at the end, maybe, you know, you see slightly higher with ICUDEC. So an equivalent of 38 units a day, obviously given as weekly though, compared to 35 units a day. And then if we look at hypoglycemia, and I think I mentioned this before, probably I like to just look at that bottom line, combining level two and severe hypo, slight increases, but these numbers are just so small anyway. And there was no significant hypoglycemia really to be said there. And the last trial I want to talk about is ONWARDS-IV. So this was a trial in patients on basal bolus insulin therapy. Again, patients with type two diabetes. Compared ICUDEC to insulin glargine, given once daily, these patients could be on oral agents. In fact, in both of these studies, and I mentioned before, they were on sulfonylureas. Those were stopped. Other oral agents, other than anything that wasn't an insulin secretagogue, was stopped. You see similar reductions in A1c, quite comparable target attainment with respect to A1c of less than 7%. And very similar also with respect to the continuous glucose monitoring parameters. And in this trial here, if we look both, kind of above there is all the hypoglycemia. Very similar with respect to the event rate and the incidence of hypoglycemia and nocturnal hypoglycemia. And at the end of the trial, fairly similar. Slightly higher doses with insulin glargine. This was kind of interesting, if you really dig into the paper. Although in the glargine arm, if you look at the total insulin dose of basal and prandial insulin, it was 80 units compared to 73 units. If you look at the basal insulin, it was higher with ICUDEC than insulin glargine. Really, this increase was more prandial insulin with insulin glargine use. And this could have to do, again, also with the longer half-life of insulin ICUDEC. And maybe in some of these patients, the glargine's sort of running out and them needing more prandial insulin. So to summarize, insulin ICUDEC and Epsitora are novel, once-weekly basal insulins that are in clinical development. Molecular modifications, applying different techniques or technologies. So one is fusion to the FC portion of an IgG. The other is having the 20-carbon fatty diacid moiety that binds to albumin reversibly. But you get once-weekly dosing. In published phase two trials, we've seen similar or improved glucose control with no increased risk. I would say of clinically significant hypoglycemia. Some of these trials did show some increased risk in level one hypoglycemia. The phase three onwards clinical development program for ICUDEC has completed. And this is under regulatory review. And QUINT, the phase three program for Epsitora, is ongoing. All of the trials are enrolling or enrolled. And the program is expected to complete in 2024. So with that, I'd like to thank you for your attention and turn it back over to Galindo. Thank you. Thank you. Thank you very much, Carl. So it is clear that there is a need for weekly insulin. So Professor Carl Weichand showed that it's indeed a clinical need. And then thank you, Juan, for presenting all the data. You know this is still in development. But you can see that we're excited. And I know you are excited as well because that's why you're here. So you want to know about all this new and novel technology. But there are many questions. And that's what we're gonna try to talk now. So we're gonna try to go into what it really comes down to when you have the patient in front of you. So the science is terrific. We're very excited. And thank you for coming again. But now we're gonna be talking about this specifically. So in reality, we anticipate that this is gonna be the next landmark in development of insulin. So we're talking about 100 years ago it was developed. And we had gone from injecting massive doses to going to weekly insulin. This is technology and a lot of work, right? So if you talk to the University of Toronto faculty, if they were expecting to have a weekly insulin within 100 years, they probably wouldn't be able to say. Anyway, so we're very excited about it. We know the convenience and the less burden to patients of using once a week. It makes total sense. And we're very excited that it's gonna be, I mean, we're hoping for this to be very well taken by patients. And we want to get feedback from you on this topic. We expect that weekly basal insulin is gonna also improve adherence. And of course, if you improve adherence and patients are taking the medications, they will have better outcomes and better glycemic control. We're gonna be doing some polling. Be ready. You're gonna be asking a few questions. And then we're gonna be discussing. And this is what I was thinking. So we're gonna need to know is my, I have some concerns. I have some expectations. I have some excitements. Is it the same for you? And that's what we want to hear from you. Do we need to work a lot on patient education? Do we need to work on clinician education or both? Is it safe? I mean, one show really excellent safety data with regards to hypoglycemia. Weight gain are really a big issue so far based on the data that has been presented. Do you believe that weekly insulin is gonna overcome this clinical inertia that we see? Maybe we're not doing the inertia ourself. Maybe it's somebody else because it looks like you are very interested. So, because I know the questions and the concerns and the comments and the expectations are related to all of these new molecules, I'm gonna bring it down to how it works, right? And of course, we have more data from iCodec because it's completed phase three. But as you told, it's on phase two. We have some data, but it's still in development. So, this is a very nice paper. It was published a couple of years ago and it's a representation of how this works. So, there are four graphs, A, B, C, D. I'm sorry, A and B. A has one, two, three, and four, right? So, A1, so the first graph, is after the first injection of weekly iCodec, right? So, it goes into the subcutaneous tissue, a few molecules into the circulation, and then down there, you see the glucose uptake and the receptor activity and the clearance of insulin, right? So, not too much of that happening because it's the first injection. So, after seven days, remember, we're doing weekly basal insulin. If this sounds interesting to you, it sounds super exciting to us because it's weekly, okay? So then, by day seven, you already have more of those little insulin molecules going into the circulation, and then some of them are getting to the receptor, and then some of them are already going through the clearance, okay? Which is different to daily, as Juan explained. This technology that was used is, in part, to decrease the clearance of this, okay? And then, on the B side, on the left, on the left side, the B graph is showing a representation that I'm gonna explain in a second, for one, two, three, and four. So, right now, we're on second dose, which is like day seven. So then, going back here to day nine, you see that there is more of these molecules going into and getting into where it needs to go. And then, after 30 days, you see that we have a much better pull, and then probably closer to being already on the steady state levels, all right? And then doing what is needed. So, I wish I, oh, sorry. I wish I can use the pointer, but anyway. So, what I want to show you here is, on that graph on B, in the vertical axis is the glucose lowering effect, right? And then, horizontally, is one, two, three, four, five weeks, okay? So, remember, we're doing weekly injections. So, zero, you know, first dose, you see there, and then it's comparing ICODEG with Galargin, right? So, Galargin is that little brown with a lot of spikes and downs, up and down, and that is basically reflecting the pick-to-throw ratio that Juan was explaining that is different. So, we have more oscillations, okay? And then, for ICODEG, yes, it takes a little bit longer to get there, to that glucose lowering effect, similar to Galargin, but when it gets there, there is much less, right? So, that is basically what Juan was explaining, the pick-to-throw ratio is much better, and it's basically giving this, close to physiology, flatter profile of basal insulin, okay? So, and then, basically, it takes about the four stages to get there, all right? So, if this clarifying how it works, and how it gets there, and how it happens, because this is actually what explaining why we need a loading dose, all right? So, you see, with daily dose, you get there with a much faster glucose lowering effect. With weekly, you need some time to build up, okay? And this is similar for Fitora, and this slide is still using the BIF term, but it's basically the same. It's a relative average insulin concentration on the vertical axis, so it's insulin in the vertical axis, and then, horizontally, we see in time in weeks. As you see here, this is, in blue, is with the loading dose, and in red is without that loading dose. So, as you see, when you do the loading dose, you get there faster, but still, it takes some time to get there, all right? And this is basically what we were explaining before, that the pick-to-throw ratio of daily insulin is one to eight, but if you compare that to Fitora, it's one to 1.14, so it's much lower, so giving this ideal physiological profile. So, we very, and then, of course, when you get there, you have a consistent and predictable glucose control, as expected. So, let's just do the first case, and then bring this to your clinic. So, remember, yesterday, when you were in clinics, or the day before, if you guys took a day off, but, so, who hasn't seen this patient? And first, we're gonna discuss a patient that is insulin, already on insulin, and the second case is gonna be insulin naive, because we do want to hear from you what you think about this, okay? So, this is a 60-year-old male with type 2 diabetes, about 15 years, BMI of 30, referred to us because their glucose are all over the place. How many of you got this question yesterday? Too many. So, they have hypertension, they have hyperlipidemia, so they're taking one or two medication for high blood pressure, one medication for high cholesterol, and their A1c is about 8.2, and the fasting glucose is 145 to 180. So, this guy is not controlled, and taking many medication. He's taking metformin, he's taking EMPA, he's taking semioral, and he's taking Glargine 25. How many of you have patients on 25 units of Glargine a day? How many of you have 100 units of Glargine? I hope nobody. So, anyway, so this is a very typical case in the practice, and the reason I'm mentioning numbers is because we're hearing these big doses, and these are not big doses. These are large number of units. So, it's a different concept. It's not that we're giving them a big dose. It's just that the units are larger, because it's a dose that takes a week. But it's not that we're giving them too much insulin, okay? So, anyway, so he reports that he's busy, he has a very complicated lifestyle, he's rushing in the morning, and so, I mean, I can see this in my life, and then he's tired at night after coming back from work and commuting, and he's missing insulin doses. So, this is probably what Carol was showing before. So, will you recommend basal weekly insulin to this patient? Do please pick your answers. So, which of the following is the biggest concern in changing this patient's insulin to a weekly formulation? Remember, he was taking basal insulin, three other doses, A1C of 8.2, high fasting glucoses. Okay, what are the concerns? A, the patient may not want to take weekly insulin. B, the patient may be concerned with a large number of units, all right? I'm unsure of the benefits of weekly insulin for this patient. As a clinician, I'm unsure of the rationale and feasibility of the loading dose. I'm uncomfortable with the dosing and the titration scheme for this weekly insulin, and I'm concerned with the busy work-life schedule of this patient and resource-missing doses, or taking double doses, okay? So, Carol, Dr. Washington, what do you think? Would this patient be a good potential candidate for weekly insulin? Oh, absolutely. I would offer this patient a way of taking a medication that he could tie to some weekly events. I mean, much like we've seen with our patients on GLP-1s, going from once daily to once weekly, it improves their quality of life. They frequently do better. So, I would- Excellent, would you be concerned that he says that the number of units is too large? I would do the math with him. You would do the math? I would do the math and just demonstrate that he's on 25. Now, I was just- One, what is the math? So, what is this math that we're talking about? We're talking, I would do, I would show him how much he's taken times seven to demonstrate what he's currently taking every week, and then suggest that it would be equivalent, or preferably, I'd probably start around 20% lower because he's not taking his injections. So, okay. So, experienced clinician, being careful. Juan, yes. I do the math myself. Okay. This person's dose would be 25 times seven times 1.5, which, I just did the math, 262. So, I'm always, anytime I see a patient, I've done all these trials, you know, I see a patient come in, I'm always dividing by seven to try to get it back into. So, I think it is clinician education, but like Carol said, we've got to really explain to the patient, you are going to take 262 units of insulin today, and this is why, and you will be okay. So, so far, maybe the questions are not right. So, it looks like, I want to make sure, are clinicians concerned about the large dose, or patients will be concerned? Clinicians are concerned about the large dose. But you guys think it's the patient who's going to be concerned? So, mostly, mostly, mostly the patient will be concerned. I think some primary care physicians will be concerned. All right, all right. Personally, yes. I mean, no doubt, these are expert diabetologists, some of them are seeing 100 patients with diabetes a week. So, it's okay, let's just move on. So, let me just explain a little bit of how the dosing was done, okay? So, again, phase three, iCodec, so, so basically, this is copy from the papers, because this is a new, everything, I didn't want it to be interpreting anything, so it's basically very straight from the papers. So, one unit for iCodec has a compatible glucose-lowering effect to one unit for the comparative on basal insulin. So, for insulin-naive patients, insulin-naive patients, at randomization, the weekly dose of iCodex correspond to seven times the once-daily dose of their basal comparison. So, that means, remember, this patient was on 25, times seven, that's the weekly dose. That's what Juan was doing. Of course, he can do it in five seconds, and by now, he just told us that nobody gets hypoglycemia, so he may be more comfortable with it, all right? And then, on ward one, three, and five, patient, because these are patients that were naive, so they started on 70 units, so this is 70 units, okay? And then, people that were, patients that were basal insulin-treated before, so switching from once a day or twice a day, a randomization, they have the dose baseline multiplied by seven, so that is clear. The next step is for the first injection, and only that time 50% of the dose was administered. This is what we're talking about, this loading dose. All right? So they needed whatever number plus 50%, okay? Again, it's not a big dose, it's just a lot of units, okay? And then sulfonylureas and glenitis were stopped, okay? This is just to clarify a little bit. And this is basically what we learned from phase two on the iCodec, right? So here is fasting glucose, and over weeks, okay? And this is iCodec with the 100% loading dose, iCodec with no loading dose in, I'm not really good with colors, I guess that is orange, and then enlarging in green. So if you see there, if you don't use this loading dose, there may be, the patient may have less fasting glycemic control for a few weeks, because of course, you need some weeks to get to steady levels, okay? But if you do the loading dose, you control them, and we already show you, and I'm gonna show you data now, that there is no increase in hypoglycemia. So this is being developed safe, all right? And the investment from the company is humongous, so they need to do it right. I mean, I trust them until I see the data. So anyway, so what I'm trying to say is the following, right? So then, the similar situation is with efitora, and this is an in silico simulation, where again, fasting glucose, vertical axis, timing weeks are horizontal, and then in green, you see there the fasting glucose targets, right? So in black, you see the daily basal insulin, and then in blue, you see the weekly insulin, and of course, the first graphic with the loading dose, you get there, you get sugars, I'm sorry, the black dots is the sugar getting into target. If you use the loading dose of efitora, you get everybody into target, but if you don't use it, you have some glycemic, that is not really well controlled, the fasting glucose for a few weeks, because of course, it takes some time to get to steady levels, okay? So what else I'm showing you here? All right, and then how it was titrated, I think that Juan explained this a little bit. So yes, the dose in the titration was 20 units up and down, and that may look a lot, but if you divide that by seven, it's about three units a day. So it actually really, what we do, and sometimes we actually do more than that, right? So, and this is the titration from the iCodec phase three, a couple of papers already published on this, so very simple, very down to earth, very similar to what we do, the only difference is that it's once a week, all right? And then, just in case, because doctors were very concerned that patients don't know what they're doing, and sometimes we don't know what we're doing, they did a study, and this was by Tom Peaver in the University of Graz in Austria, double and triple doses of insulin, all right? How many of you have patients that have received two doses of daily insulin? A couple, okay, just a few patients. Anyway, so I don't plan to discuss this study per se, because it's complex, I want to show you, but anyway, so type two patients on basal insulin, orals, A1C less than 9%, they got two, three doses. What I want to show you is this, all right? So this is double and triple doses of iCodec versus Glargi 100. I'm sure that this was not done when the MPH and Glargi was in development, there was not that many concerns, so anyway, so this is extra safety data that we have. So on the right is double dose, and next is triple dose. In blue is iCodec, in that color that I cannot say, orange is Glargi, and then as you see there, similar hypoglycemia, and then this is a study that was also measuring counter-regulatory hormones, because the concern is that, will this patient recover from hypoglycemia with a weekly insulin on board? Yes, they recovered the counter-regulatory hormones, responses to hypoglycemia was similar in both insulin, and probably a little bit better in iCodec, based on this study. So if there was anybody concerned with titration, if there was anybody concerned with double and triple, there is some data showing that it's supposed to be safe. So do we need more data? Of course, we're clinicians, right? So we'll need more data, but this is just to reassure you that there is some safety there. So case two, so this is an insulin naive patient, 58, type 2 diabetes, 10 years, BMI of 28, A1C of 8.8, metformin, ciragliptin, DAPA, he couldn't tolerate GLP-1. Indeed, we see this every day in practice, how many people we want to continue the GLP-1, but they cannot, they may need something else. Would you recommend basal insulin, weekly insulin on this patient? You think that this patient doesn't need weekly insulin? What would you do? Would you add on basal daily insulin? Would you add on supranurias, and do please click your answers, adding weekly basal insulin, or re-challenging with the GLP-1? What would you say? So I don't know if the answer is right, but there is some programs in development combining weekly, both, weekly, both. So anyway, so, all right, some more people will re-challenge with GLP-1. And then some people will do daily basal insulin. All right, so that means that instead of first going to weekly, you will consider daily? So I work in a county hospital, so I also need to use supranurias. All right, so what do you think would be the most important to this patient? Remember, insulin naive, A1C of 8.8, taking medications, so when you do weekly insulin, fewer injections, improving A1C, improving A1C with no hypoglycemia, or improving A1C with no hypoglycemia and no weight gain. And the question is, what the patient will think? All right, so this is the same question that we discussed earlier, but remember, this patient was not on insulin. This is an insulin naive patient, so if you start weekly insulin on this patient, what will be your concern? A, the patient may be concerned with the large number of units required for weekly insulin. I'm unsure of the benefit of weekly insulin for this patient. As a clinician, I'm unsure of the feasibility of a lower dose. I'm not comfortable with that dosing scheme for weekly insulin. Excellent, so it looks like it's still the most common answer for insulin naive and people switching from basal daily insulin is that the large number of units will be a concern to patients. All right, excellent, and then still, we don't have practice with the dosing. All right, do you guys agree? Professor Weisen and Dr. Prius. You know, I personally don't think that the patient will be concerned if the provider is confident and projects confidence in the decision and the number of units and demonstrates, as Juan says, why this is the right dose. All right, so the patient will probably have no context. They won't know what that dose is. They won't know, oh, usually you start with 10 units. Why are you starting me on 70? Yeah, so, excellent point. So I know that the loading dose seems to be a little bit of concern, but right now, we're doing loading doses for daily insulin. We start with 10 units, sometimes with 20. We don't start with one unit, right? So we do 20, right? So it's a different concept, it's just as weekly, okay? I think that the need here is that the desire for basal insulin is that it mimics that basal insulin secretion. And I think that in 2021, we didn't know, but at this stage, with weekly insulin, I think that is similar. We have a distinct peak effect, so less peak there. You have a continual effect over 24 hours, so probably this is better with weekly insulin. Low risk of hypoglycemia, lower, in this case, similar. That is administered once a day or probably less, so this is much better with weekly insulin. That it allows some flexibility, so our patients are busy, they have complex lives. And that also minimizes viability and improves glycemic targets. So I think that overall, this weekly formulation will probably improve adherence, persisting, and satisfaction, and that's what we're hoping for. We just need to use it. This is a summary of what we're thinking, okay? So I went through and found the questions and you folks upvoted questions so that we just took them pretty much in order of what had the most votes. So, and I put them in order. So this is gonna be a quick fire. So a quick fire because we don't have too much time, but anyways. So the first question that most people actually ask to be answered is, do you think that less access to once weekly drugs is related to financial or insurance issues? And that is a reason for not using weekly medications. Well, I think that, you know, I think they were talking in the context of the world. And I do think that in most of the world, the cost of these medications can exceed the ability of patients to pay for it. In the United States, we have very good coverage for the once weekly GLP-1, and of course the once weekly insulin isn't on the market. All right, yeah, I mean, with respect to payers, I mean, my only, I don't know if it's a concern, but, you know, when we went from MPH to Glargine, from Glargine to, you know, Glargine U300 and Daglidec, we were getting similar glycemic control, but less hypoglycemia. So that really is a nice advantage. You know, here we're seeing similar glycemic control, and at this point, it's either similar hypo or perhaps numerically slightly higher hypoglycemia. I think it is something that in the real world, when it's available, as we've done with so many other insulins, you learn how to use it. So I think real world data is gonna be real, you know, very important, but I think it's gonna be, you know, I'm not a person that goes to payers necessarily, but I would think it's kind of a, could be a tough sell, and so I think price is gonna be important, and a lot of data are gonna have to be generated, and, you know. So for now, I want to applaud the companies for putting this effort, and I will let them discuss with payers, do please do it for us and for our patients. But I think, yeah, so the time will let us know. What happened with intercurrent acute illnesses, colonoscopies, surgery, hospitalization? Do we have any data on these, and if we have data, can we comment on it? I'm not aware of any data, but, you know, theoretically, if you are on the right dose of basal insulin, and you don't eat, and you're at steady state, you should be fine. So I would think for procedures, I mean, you can't take it away, it's there, but I think we need data, certainly in, you know, I would think in critically ill patients, no, we'll probably still be given IV insulin and whatnot, but I think data would be needed there, but I don't see a big issue if they're on the correct dose. So my answer to that question is to, like a colonoscopy prep, I would recommend that a person be drinking carbohydrate-containing fluids as part of their hydration that they're doing during the day, and then for a patient in the hospital, they may need a glucose drip, but I like one, if your patient's appropriately titrated, they shouldn't have that much trouble. Now, the problem's gonna be happening in the primary care, you know, if they're using this agent, and over-basal insulinizing them, and those patients may have more issues. So that concern was also with Deglu-Deg, and we did the study in the hospital, we titrated daily, it was published in Diabetes Care a couple of years ago, it was the first, Diabetes, Obesity, and Metabolism. So Deglu-Deg, we don't titrate it daily, we do it every, and in the trial that we did in the hospital, we did it daily, and we didn't see any issues, so I guess that the answer is we need data, but it looks like the technology is gonna give us the right answer if we use it appropriately, right? So a very interesting question that I don't think that we have an answer. So what happened in patients with high-polyalbuminemia, low albumin levels? Do you think, do we have any data? We have no data, but we do have data with the other agents that use the diacyl fatty acid moiety to increase, and, you know, so we have data with Deglu-Deg, and showing that you'd have to get an albumin level down to about 1.4 before they show any differential binding. Yep, nothing to add to that, shouldn't be an issue. You'd have to just basically have almost no albumin. I mean, this is the part of the medicine where you practice the art of the science, and you use your clinical judgment, so there is not one medication that is perfect for every patient. So you need to use that clinical judgment that we used to teach at medical school, but maybe not anymore. Is that right? So, I mean, that's what they told me, right? So any data on effects on weight? So, Juan, you presented this data, so compare it to something. Yeah, and I showed the weight effects. So there's certainly no advantage with respect to body weight. Either it's been either slightly higher, or I think, you know, in the first phase two BIF study, or F-Sitora study that we published in Lancet, there was actually less weight gain. There was a two kilogram increase and a one kilogram increase with F-Sitora, so it was actually better. But in the other trials, it's been either similar, or actually, you know, slightly higher with the once weekly. All right, so you get the typical weight gain you would get. That you would expect, yeah. Right. All right, so this question is, we're going to start with Carol first. It has to do with probably the knowledge that we have right now, versus the knowledge that we're going to know when we have weekly insulin. Why doing insulin, weekly insulin, rather than GLP-1? I would do GLP-1 first, and then weekly insulin. All right, and what about if you combine them? Because it's another question, just to kill two birds. So, this is my own perspective. I think that there's a role for a fixed dose combination of this agent, in that it would allow patients to, or providers to get, you know, one injection, and titrate, and get the best possible control, and particularly for those with very high A1Cs. But I would tell you that I really like to push the GLP-1 up to the maximum dose that the patient can tolerate before adding basal insulin. So, Juan, weekly GLP-1, weekly insulin, or both? Depends on the patient. Generally, weekly GLP-1. Okay. And then go to insulin. But as you know, I mean, there is, in clinical development now, formulation of iCodec with semaglutide, so iCosema. All right. Yeah, so it makes sense. And that gets in clinical trials. It makes sense. I don't know if we're going to be able to do the fixed dose ratios, because the titration is a little bit different. They're doing it already. No, but, no, no, but for iCodec, but I don't know for the other one. But I think it makes sense. It totally makes sense from the physiological standpoint. Yeah, I think so. All right. So, and then the last question, how to come off weekly insulin to go to daily? So any data on that? I don't have any, I cannot say too much, because I'm confused. I haven't seen any data, but I have done other very long-acting insulin studies in the distant past, and it worked quite well to start the daily at a percentage of the final dose, and then gradually increase the percentage over time. And so I just look at the pharmacokinetics of this medication and probably start the week after the last injection, start them at 10 or 20%, and then gradually just increase the dose, double the dose every week until they get out to the five half-lives of the drug. I want to ask you a last question. Who do you think would be the ideal candidate? I think there are probably several good candidates. I think the patient who either, like your last patient here, has not tolerated a GLP-1 receptor agonist, needs an injectable agent, and this could be added. They're already on a GLP-1 receptor agonist, not achieving control, and you're thinking about basal insulin. Why not? If it's more convenient and it's accessible. But I also think, again, I'm gonna go all the way. Someone who's missing their doses, like this first patient you showed, and taking once daily. So it needs the convenience, and I think ultimately it will prove to be better in the real world. So a lot of different candidates. Carol? Well, we don't have any data that has been published with type 1 diabetes yet, but I actually see the patient with recurrent hospitalizations for DKA, it'd be perfect. Send a visiting nurse out to give a once weekly dose. They're not gonna be in great control, but at least they won't be in the hospital. Teenagers and people who are notoriously bad about taking their insulin, and they could definitely do that on their way to church or something. Patients requiring help, so patients who are disabled, either physically disabled, unable to give their injections, or just can't inject themselves, as well as elderly, so that the family members could be... Or nursing assistants. Yeah, exactly, so that they don't have to try to do something on a daily basis. But saying that, those are patients who it's a slam dunk. They will be candidates for a once weekly. But I have several patients who are on once weekly GLP-1s, who think that the GLP-1 is insulin, and they are like, I can't believe you got me started on that once weekly insulin, or they are on daily something, and they say, can I take the once weekly insulin? So there's interest that people think we already have it, and they're really interested in doing it. So I think the patient concerns about dosing can be certainly balanced with the excitement that they have in being able to cut back their injections. Excellent. Why not to give loading dose to everyone? So the studies have been done in different designs. The study presented phase two had different designs to learn, but phase three has been done very similar. Like for hypertrophy, I'm sorry, but I don't think that we're gonna have data on that for some time. You need to use it. You need to use it for some time before you get that complication. Thank you, Dr. Juan Frias, Professor Juan Frias from Los Angeles. Pleasure always to be with you. Thank you, Dr. Wesson from Washington. Thank you.

once-weekly insulin formulations

type 2 diabetes

Epsitora

insulin Degladec

insulin glargine

glucose control

hypoglycemia

weight gain

patient adherence

iCUDEC

GLP-1 receptor agonists