Dr. McNerney identifies the stages of Type 1 Diabetes, describes upcoming T1Dm immunotherapies and the immune response. He also disciusses Teplizumab treatment in preventing progression of T1DM.
Good morning, everybody. So yeah, so, I'm Kyle McNerney. I'm pediatric endocrinologist at WSU and I spoke at Early Bird Rounds a few years ago about our new outpatient type one diabetes education program, which went live in the middle of 2020 and has been a success so far. So hopefully, if you've referred anyone for type one, we're still doing the majority of our education inpatient, but for the right candidates, um, we'll do that new onset education as an outpatient. But today, I want to talk about Type one diabetes again, but more of a focus on antibody screening, because a lot of development has been made there, and some new guidelines are currently out that suggest we need to be screening more, and the ones that are coming in the pipeline suggest potentially even screening the general population. So there's going to be a lot more questions and interest in antibody screening, even in the next couple of years. I'm also gonna talk about an immunotherapy that um we offer at Saint Louis Children's Hospital, which is tlizumab, which has been FDA approved to delay the progression of type 1 diabetes. So you'll hear about those two topics. And a few other bonus things. We do not have any, I do not have any disclosures today, and here's my objective slide. So yeah, I mentioned, we're, we'll talk about staging type 1 diabetes. We're gonna talk a lot about antibody testing. We'll talk some about the type 1 immune response and some different type 1 therapies, uh, the role of C-peptide, because that's an outcome that's going to be in all of these immunotherapy trials, and then we'll talk more specifically about tlizumab treatment, if that's come up. Uh TZ is the brand name, uh, for preventing progression of type one. And I've got a poll out there to see, have you sent type one diabetes antibodies testing. And I'm curious how that will look, in part because if you haven't sent it yet, you're going to be asked about it, I think, in the next couple of years, uh, because it, it really looks, looks like the future for screening for type one diabetes. All right. So when we look back, you know, it's been a little over 100 years now that we've had insulin. And prior to insulin therapy, of course, children, unfortunately, this was a fatal disease, you could treat with a starvation diet for a little while, but in the end, um, type 1 diabetes was fatal. With the discovery of insulin in the early 1920s, uh, suddenly patients, as you can see here on the right, were treated effectively, and so it's, it's been a miraculous discovery. But not a lot has changed in the type one therapy landscape since then, right? We've, we've had an insulin variety 100 years. Now, about 4 years ago, we started having tiplizumab or TZ as an option, but really, we haven't had any way to intervene with this immunological disease to actually address the underlying immuno, uh, the immuno, give, give an immunotherapy to actually treat this condition rather than just kind of give a band-aid of insulin, which treats the symptoms of high blood sugar and replaces the deficit. So, first, we need to talk a little bit about how and when we diagnose diabetes. And historically, everyone was diagnosed in what is now called stage 3, type 1 diabetes. And that's the classic diagnosis. You come in with polyuria, polydipsia, polyphagia, significant. Weight loss, significant dehydration, and about a third to a half of kids come in in type 1 diabetes. And what's interesting is that, that actually hasn't changed much over the past several years and past decades. DKA is still quite common, up to about 50% of new onset type 1 diabetes. And when you, of course, come in in DKA, that's a very severe, um, can be fatal condition and needs very uh prompt medical assessment. And there's no reason we have to catch so many kids in DKA. It can be detected earlier, and that's why we'll talk about these earlier stages of uh diabetes. So when we look at those classic diabetes criteria, we're talking about A1Cs 6.5% and above, fasting plasma glucose, 126 and higher. If you were to do an OGTT you'll have a 2-hour glucose greater than 200. And then often you'll have these symptoms of high blood sugar with a random plasma glucose of 200. So that's the classic definition. But what we've learned is that there are earlier ways to detect type 1. So I mentioned, we've been detecting everyone at stage 3. So here on the right, you can see stage 3. We now have earlier stages, we can look at type 1, and now it's a lot more appreciated about the background genetic risk. You know, there are people who have a genetic programming from birth and their HLA type specifically, that puts them either at very high risk or very low risk for type 1. And so, you know, using genetic scoring, looking at their HLA types, we can start to understand that. But really where we're looking to detect um early type one is trying to catch that immune response. So, after you have this genetic background that puts you at risk, most commonly, it's being an immediate family member of a, of someone with type 1, that's how we identify most of it. All those immediate family members have about a 15 times greater risk than the general population for developing type one. So we know some of the genetic background from there. After we get that immune activation, what we're really looking at is the immune response in terms of circulating autoantibodies. So there's 4 commonly sent autoantibodies for type 1 diabetes, and if you detect 2 or more antibodies, that person has a basically a 100% chance of developing diabetes. And the question then is just when they're going to start insulin, not if they're going to need insulin. And you can stay in that early stage, just having antibodies for several years, but at some point, you'll start to develop abnormal blood sugar, and then we call that stage 2, and then stage 3 is, of course, when you start insulin, and stage 4 is just long-standing diabetes. So, breaking that down a little bit more, I mentioned there's 4 antibodies, and that defines um stage one diabetes as having 2 or more. So you can see that here. We typically are sending the GAD 65, IA2, ZNT8, and an insulin antibody. There are some more research antibodies out there as well. And if you have 2 or more of these, again, 100% risk of type 1. I'll talk a little bit if you have one antibody, because that is a little bit of a gray area, and then of course, if you have zero antibodies, that's generally reassuring and lower risk for type 1. Stage two, I mentioned you have those antibodies with dysglycemia, and how that's defined, it can be a mild elevation in A1C, so 5.7 to 6.4%. It can be a mildly elevated fasting glucose, 100 to 125, or probably most importantly, in terms of catching this stage, if you were to do an OGTT they wouldn't go up to 200 or above, which is the stage 3 diagnosis, but it wouldn't be totally normal, which is at 140 to 199 at 2 hours. And often that's the, if we were to do more OGTTs, that's when we would actually catch stage 2, type 1 diabetes. And why we care the most about stage 2 is that it's a brief window period where the immune system is highly active. It is actively destroying, um, the insulin. Making cells, the beta cells, and it is typically a brief window on your way towards insulin dependence. And because it's that unique period where you're about to need insulin, and your immune system is highly activated, it does seem to be a very potent window we can intervene on with immunotherapy. And then I mentioned our stage 3 over here. So looking at this chart, this kind of gets at the uh probability of diabetes over time with different autoantibodies. So you can see down here, zero autoantibodies, overall, a low-risk group. Of course, it could happen, we can never say never, but a lower-risk group. One antibody puts you in this medium-risk probability of diabetes, and then you can see 2. 2 or 3 autoantibodies, that probability of diabetes over time, you know, this is a 20-year graph in one small population, but it showed it, it, it approaches 100% over, over those two decades, and different studies all confirm that it heads up towards 100%. How quickly you get diabetes is very, very individualized, but um if you have two or more, you are going to uh develop type 1 diabetes. OK, so who are we talking about screening for type 1 diabetes? What's the role of this test? It's right now, it is predominantly used for those with an immediate risk of type 1 based on an immediate family member of type 1, who has type 1. So again, they have about a 15 times risk, the general population, and recommendations for screening typically start at about age 1 is at the lowest, um, age 2 and up is more common. And what that looks like, there's multiple ways to test antibodies. I have a slide on that coming up, but um it is a blood test of some sort. There are some at-home kits now that can do that blood test, and that's what most of our families with with type 1 do. Um, they'll order a kit through TrialNet or Ask are the most common ones, and then they will do that testing at home for children is often the group they're testing. Um, you can also add on antibodies to any venous blood draw. So when we're seeing patients in clinic and, you know, sending thyroid testing or CBCs, BMPs, anything, we can add on these, um, type one diabetes antibodies as well, and I'll show you how to order that in Epic. But um that's the, that's the group that's clearly it, this is valuable information for. The group that's not as clear on is if you have a personal family history of autoimmune disease, specifically thyroid and celiac are high-risk conditions, type one diabetes antibody testing may be extra um useful in those. And then I think the question which has not yet come out And any consensus guidelines is, is, should this be some, a part of routine screening, like with a cholesterol panel, um, should we also be getting type one diabetes antibody testing? And ISPAD is an international group of, uh, diabetes researchers, and they are looking at more, more closely recommending everyone obtain type one diabetes antibodies in their lifetime. It is, of course, a, a lower, you know, a low probability event for most families, but it is a life-altering diagnosis, so we'll, we're following up on it that will be more recommended for the general population. I mentioned if negative antibodies, most of the time, we will then defer additional screening, sometimes, especially in high-risk categories. If you do have a family member with type 1, you could consider repeating that screening. Some places have recommended um repeating every 3 years until the age of 18. OK. So I mentioned single antibody positive patients are a little bit of a gray area. If 2 is 100%, a single antibody is probably about 15%. So it is a significant chance, but um what we, what we know the most about single antibody positive patients is that There's a risk of progression to two antibodies that often occurs pretty quickly, and if they don't progress to two antibodies, they often, on the flip side, revert to zero autoantibodies. So we can often pretty quickly um kind of hash out, are they moving into the high-risk zone or the low-risk zone. And so that's about 50% actually revert to the low-risk zone. So our first recommendation if you have a single autoantibody is typically just to repeat it, and we'll see, did that go down to zero, putting them in the low risk risk category, or are they one of the uh progressors? And often within 6 months, they'll go to 2 or more antibodies if they are a progressor. And I mentioned that overall, 10 year risk of progression is about 15% for a single autoantibody child. So, what does that single antibody testing look like for follow-up? Um, the younger risk kids or the younger age children are higher risk, so there's recommendations to repeat that antibody panel every 6 months for 3 years, if you're below 3 years of age, and if you're older than 3 years, you can repeat testing annually for 3 years. And you're basically waiting to see, well, do they stay with one antibody, in which case you keep testing. Do they go to 0, which Um, you know, my comfort level right now is if you've gone back to 0, I don't typically recommend any more repeat screening, or they, um, in that group that progresses to 2 or more antibodies. So that's really what you're kind of waiting for to see, that's that screening interval. To me, it does seem um burdensome, but not everyone is going through that testing serially, repeating and repeating, repeating. You're really just kind of waiting to see, are they flipping to 0 or going up to 2, and hopefully they distinguish themselves uh pretty rapidly. OK. In terms of type 1 diabetes antibody screening, so, you know, at through SLCH Cerner Labs, we typically order this diabetes mellitus type 1 evaluation with that epic test ID and that will get those 4 antibodies I talked about, and they'll do a send out typically to Mayo. Right now, it's going to esoteric, but it'll flip back to Mayo pretty soon. Um, but they're all, you know, reputable labs that will get you an answer, and again, If it's 2 or more, 100% risk, 1, medium risk, and 0%, low risk. Quest has similar antibody testing, they have a diabetes type 1 autoantibody panel, and LabCorp does have the diabetes autoimmune profile as well. I mentioned those at-home kits, so that's what I highlighted down here. And this is where most of our families who have type 1 in the family, this is how they're proceeding. Um, they order it through TrialNet, which is a research organization that's looking to do, uh, well, they, they run several landmark trials with type one prevention. And this will get to them as a home kit with a, you know, a FedEx envelope. They have to do a blood test on the finger. It is bigger than a typical blood sugar test. It's more of that lance, um, more of like the sharp razor blood draw that gets a lot of blood. They'll have to apply it to filter paper, um, fill up a few circles on filter paper, put it back in the FedEx envelope, and then get it sent off, and then within a few weeks, they'll get their, um, antibodies. Results, and they get delivered right to the patient, and they do also get delivered with counseling and, um, you know, information on what to do if you have two or more autoantibodies. So, it, it's nice because the result comes to the patient, but also the next steps come to the patient as well, and then they share those with us. Um, ASC is another major tester for our kids, and ASC is actually run through, uh, Colorado, so it's autoimmunity screening for kids. Anyone can do it. You do not have to live in Colorado. But they additionally test celiac. So if anyone has type 1 and celiac in the family, I do preferentially have them go, uh, do their screening with A, because they'll do that uh tissue transglutaminase antibody for celiac. All right. Let me review the poll before we move into immunotherapy. So, OK, the, the vast majority of people have not sent type one diabetes antibodies, which is common and what I'd expect. So 86% have not, 14% have. Um, so that's great. So hopefully now you've learned a little bit about type one diabetes antibodies. So if you were asked To send it, or you see those results, you can understand a little bit about their risk stratification. And then at the end, I'll also specifically say, you know, who do we want to see in endocrinology, which is the short answer is, anyone with 2 or more antibodies needs to see an endocrinologist because if you've got 2 or more antibodies, you're going to get type 1. All right. So let's move on to the immunotherapy and the type 1 immune response. So, in type 1 diabetes, again, it's, it's an autoimmune disease where you're destroying those insulin-making cells, the beta cells, which are pictured down here. The actual, you know, attack is from these killer white cells, these T cells, but there's antibodies being produced in the blood that actually help them to target, um, and are a marker for destruction, um, in particular for those beta cells. So when we talk about an immune response, we're either, either talking about T cell therapy. B cell therapy, or we're just trying to protect the health of these beta cells, and there's, you know, a lot of studies looking at how diet or metformin or GLP-1s or verapamil can actually um modulate the, the death and destruction of the beta cell itself. Let me grab one question from the chat. So the question is from Doctor Porter, are the home tests free to the patient and only require them to do the finger poke themselves? So, yeah, let me go back one slide. These two at the bottom are free to the patient. It would just be um Filling out the paperwork because these are both research type um studies. So they don't have to engage in research, but they do have to do that, you know, fill out the paperwork and then they're eligible, particularly with TriNet to do research in the future. So those two are free. These top 3 type 1 diabetes antibodies are actually reimbursed extremely well and normally. It's not an exotic lab test in which we're thankful for. It, it used to be, but now insurance um companies are widely covering this testing, so it'll just be, you know, similar to any other lab test, but not outrageously expensive. Um, and then, yeah, the finger poke themselves. Most of the families that do this have someone with type 1, so they're familiar with that. Um, there is actually one I didn't share about here called Enable Biosciences, which has a kit where the whole point is to do an in-office test, um, and that would be, you know, the physician's office doing the finger poke for the child. Most families though, And actually end up doing the finger poke pretty well, you know, with or without type one history, like, they, they, they, it tells you how to clean the finger and operate the device, and it is, you know, a little bit more painful than the average finger poke, um, to get a little bit more blood out, but, um, kids overall do well with it. And if there's any concern about that, well, I'm not sure if they'd be better with phlebotomy, but I can often say, hey, let's get these antibodies ordered, and the next time you have to do any type of venous blood draw, um, for any other reason, we can get that antibody set with that. All right, so we'll move forward to C-peptide. So C-peptide, the major reason to know about it is because all of our immunotherapies that are in development and currently exist, tlizumab, they're all looking at C-peptide as an important outcome. And so C-peptide, it's co-secreted, um, it's part of the insulin, uh, pro-insulin, insulin and pro-insulin basically come with C-peptide attached. And C-peptide circulates in the blood, and so we can use that, especially for people who are on insulin, as a surrogate marker for insulin secretion. And what's fascinating about C-peptide is that Even long-standing uh people with diabetes, they actually continue to make a little bit of C-peptide. So, 80% of type 1s have C-peptide detectable in their urine, even after 18 years of diabetes or longer. So, we know that you can still make a little bit of C-peptide. Clinically, It's always questionable how much that little bit is important, but it actually does seem to have a role, and the more residual C peptides you have, well, the easier your diabetes is to control. So people with greater residual C peptide have better A1Cs, fewer complications, and decreased risk of severe hypoglycemia. And preserving that C-peptide is important because here's a nice C-peptide marker over time for different age groups. Um, you can see generally, as your duration of type 1 diabetes in months increases, there's a decline in your C-peptide. You see that what we call this honeymoon phase initially, where your C-peptide actually increases from diagnosis, and that's due to restoring normal glucose levels and helping restore the health of those beta cells. But then you see this decline over time, but still probably staying residually active. The honeymoon period does stratify differently in different age groups. So this gray bar is the older 10 to 15 year olds, 5 to 9 year olds in red, and then age less than 5 in blue, and you can kind of see that C peptide, unfortunately, the honeymoon period is not as robust, and then the decline is overall more rapid for the younger kids. All right. So, this is a long list of type 1 immunotherapy. I am going to talk about just the ones in bold on here, but I also just wanted you to see, there is a lot in development, you know, this is something that there's generally always something exciting going on with type 1 immunotherapy. Getting it, of course, to clinical trials in humans that are effective has been the limiting factor. You know, we've cured type 1 in mice thousands of times at this point, but uh we haven't truly cured it in humans yet. But uh, When we look at type one immunotherapy, we can think about it as kind of a non-specific immunotherapy. So sometimes we do have patients with type one who are also receiving, um, you know, cyclosporin or azathioprine or methotrexate. That does seem to modulate the course of their type one. All those agents have, um, pretty significant adverse effects that makes the risk-benefit of those medicines not worth it in terms of type one, immunotherapy. But if they're on it for, you know, an oncologic condition, it does modify their type one. Antigen-based therapy. There's a lot of excitement about, you know, offering the antigen itself. So oral nasal insulin, had a lot of excitement about it, hasn't really borne out to be that useful clinically. GAD 65, which is a, a beta cell marker, injecting that into the lymph node actually seems to offer some protection. And calm down the immune system effects. So there's some exciting trials with GAD 65, uh, intralymphatic lymph node injections, and then different insulin-derived peptides have been useful as well. I'm gonna talk about anti-thymocyte globulin because there's some exciting research about that coming out and some new drugs in development. There's cytokine therapies, um, here's a long list here. I'm gonna talk about two, bericidonib and verapamil, mainly because they're oral, and verapamil especially, we have a lot of, uh, experience with generally. Beta cell immunotherapies like rituximab exist. And then the most important one on this whole slide is going to be tiplizumab. So, that's an anti-CD3 therapy. That is the only FDA approved immunotherapy for type 1, and it will get some expanding indications in the next couple of years, I anticipate. So we'll spend some time at the end talking about tlizumab specifically. And then there's some other CD40 and co-stimulation blockade um therapies that are exciting. And stem cell or other islet cell transplantation is definitely um moving along quickly and excitingly, but um I won't talk about that today. OK, so I mentioned I would talk about these few in bold. So let's start with anti-hymocyte globulin. So, if you're familiar with anti-thymocyte globulin, it's usually an animal-derived serum of basically um IgG against um T cells. So it's a T cell depletion therapy. It just knocks out all your T cells, basically, and if someone's in the midst of developing type one, that's extremely effective to halt and slow down their their type 1 diabetes because the T cells are actually carrying out um the destruction of the beta cells. Unfortunately, antithymocyte globulin, it's administered over 2 days, typically an injection on 2 days, and the first day is tolerated pretty well, and then the second day, people get very sick, and that's because there's a serum sickness-like reaction that occurs um from this injection, and So when we look at, you know, the outcomes for these patients, 70% of them on that second dose, um, report serum sickness, which they might be getting fevers, they might have vomiting, they might have a bad rash, um, they might have changes in their liver enzymes, like you can get some pretty severe sickness from this. And if you were to keep giving it beyond two doses, it would likely just continue to get worse. Um, that being said, Giving antithymocyte globulin is very effective. It totally changes the immune profile. You can see the placebo lying here, had no change in their CD4 to CD8 T cell ratio, and if you're giving the medicine, you're rapidly and immediately altering it, and it's a persistent effect. You can look even past 20 weeks, they're still seeing that effect. So how does that translate clinically? Well, they'll get, this is a two-year study of um anti-hymocyte globulin from 2019, that really showed remarkable preservation in C-peptides. So here's this blue curve, is those who got that anti-hymocyte globulin, and they are just still making C-peptide two years out at a much higher degree than those who got placebo, which you can see follows that typical rapid decline. Interestingly, you actually see a, a, a significantly different A1C between these groups. So those who got um antithymocyte globulin, have an average A1C is about 1 point lower, so they're more in the 6s to low 7s, and those who got placebo are more in the 7s to 8s, and that's still a clearly different curve two years past therapy. So why I want you to know about this a little bit is because there's a new drug in development that is very similar to anti-hymocyte globulin, but they've been able to remove um all the animal components that make you have a severe serum sickness-like reaction. So there's a lot of excitement that um in their upcoming trials, we might be able to give it a two-dose regimen of something that doesn't make you horrifically sick, but also gets you all these benefits. All right. Another one just to know about, there's a lot of excitement about bericitinib. It's been a little bit tempered recently because the long-term therapeutic benefit does seem to be lost. But uh barricitinib is actually an oral JAK inhibitor. You take it once a day, has Very, very minimal side effects. Basically, it's hard to tell if you got bericitinib or placebo, so it's very um well tolerated, but even by um children down to age 10. And what they found was that bericitinib did preserve C-peptide effectively. You can see that here. It actually led to patients using a lower insulin dose overall, and again, we saw that A1C benefits from bericitinib. The only downside is that their more recent long-term extension data from this year um did show that there was a loss of that therapeutic benefit once you stopped taking the bericinonib. And then the last, uh, before I get to tlizumab, I do want to talk about verapamil. Again, I'm calling this out because it's an oral therapy that's overall very well tolerated. And if you're from, you know, verapamil, it's typically used for blood pressure management. It's a calcium channel blocker, but it actually has this unique role in the ER stress pathway, so it inhibits this TXNIP and when you reduce ER stress in the beta cell, You decrease beta cell apoptosis. So by taking this oral medicine, um, every day versus placebo, we actually can see that there is a lot of preservation of these beta cells, preventing them from dying, and then preserving their ability to make C-peptide. And we can see that data here. Um, this nice JAMA slide uh summarizes everything nicely, but, um, what I want to point out on this slide specifically is that you can see the verapamil data, baseline C-peptide, 0.66, at 52 weeks, 0.65. So, very much identical, showing excellent C-peptide preservation. The placebo fell, of course, from 0.6 down to 0.44, so followed the typical kind of C-peptide path. What I find also very interesting about verapamil is that um if we look at this, these uh box plot diagrams, we can see that there's some big outliers in terms of verapamil therapy that might suggest there are some individuals who are going to be great responders to verapamil and others who are not. So when we look at um The C-peptide data points, uh, verapamil in blue, placebo in yellow, you can see that overall the means for verapamil are higher, but at every time point, there's these outliers in the verapamil group up here, who preserved a ton of C-peptide, and you can see them here as well. There's these. Outliers who seem to be very good responders to verapamil, and we haven't, you know, been able to identify who, who responds to the best, but it's clear in all these type one trials that there are unique individuals who respond uniquely to different um medicines and immunotherapies, and again, just points out that Everyone's type one, and their staging of type one is a little bit different, and the ability for having precision medicine for immunotherapy is very exciting. OK, and with that, we'll turn to the last part of my talk, which is going to be about tlizumab, and then, you know, some final recommendations for antibody, consensus screening, things like that, and referral. But uh let's talk about tlizumab. So, everything else I talked about with immunotherapy is very much coming, you know, in trials, it's exciting, but we're not using that clinically. Talizumab, we are using clinically. So tlizumab is the brand name TZ, it's a Sanofi drug. And it's an, I mentioned an anti-CD3 monoclonal antibody, so it's a T cell therapy, and it seems to specifically boost um T regulatory cells and deplete those killer T cells, and that combination basically halts or slows down the progression of type one. There are some things to know about topozumab, so I actually started with the adverse effects because, you know, they, they are notable. The major one is that this is not a benign, take a pill once a day therapy. This is a, a commitment. You do a 14-day course of daily IV infusions, and it covers you every day of those 14 days. So, Monday through the weekend, Monday through the weekend, uh, we always start them on Monday, and then you're done. Right now, the indication is just to give this course once. There have been some trials looking at giving it. Once and then again 6 months later and potentially seeing benefit from that. While receiving this um medicine, we have some known adverse effects. So you do see lymphopenia quite commonly of 78%. That actually is a feature of the drug working. So I mentioned it's got to deplete these killer T cells and boost these Tregs. And by, while you're, the sign that it's working is actually seeing this transient lymphopenia. By the end of the two-week course, um, it has almost always rebound. We do watch it closely to make sure it doesn't get to a critically low level during infusion. There could be a role for halting or um delaying the infusion if it were to reach a critically low level, but everyone gets some degree of it, but then it uh typically rebounds to normal by the end of those two weeks. rash is seen in a third of patients. A severe sepsis-like syndrome called cytokine release syndrome, unfortunately, it has been seen a few times, so about 5% of subjects. And cytokine release syndrome, it's, if it were to happen, it basically looks like an anaphylactic or a sepsis-like response that needs to be monitored in the in the hospital or IVU or ICU. Um, infections have been pretty similar between tlizumab and control, so indicating though it is an immunotherapy, you know, it, it wasn't dramatically increasing their risk, um, from general infections, and then specifically in all the tlizumab trials that were occurring from 2020 on, um, COVID did occur at similar rates in both groups, and there wasn't a difference in terms of their COVID infections either. So why do we give it, you know, what's, what's the point of giving this medicine, it's burdensome. Well, it really seems to alter immediately their progression to insulin. So this trial, this shows um a TN10 trial from 2019. This was the data that got it approved, FDA approved, um, and we're looking at a Kaplan-Meyer curve that's showing how many people are free of type one diabetes, though, so the proportion who don't have it. So at the beginning, no one has it, so 100% are free of type one. And what you can see is those who didn't get tlizumab, their curve immediately separates. Many of them went on to get insulin within um a few months, and then they continued to require more and more insulin over time. The tlizumab group, that high-risk stage, especially those next few months, it immediately kind of protected them. It was very rare to get To progress to needing insulin for at least that first year, and then the curve kind of matches it down similarly. So, when I mentioned, oh we give it once right now, but maybe we should give it once, and then again in 6 months or a year, this is why that looks compelling, because you can see those curves immediately separated, but then did unfortunately start to match each other later on. If we could keep intervening here, could we keep this curve high, high, high, high, and then slow that progression down towards type one? Um In terms of numbers, this is basically a 2.5 year delay on average if you got to lizumab versus placebo, and for a lot of people, I mean that's very meaningful to say. We can buy you an extra 2.5 years where you won't be taking shots every day, and in my mind, it's kind of, you load up the The, the painful point of the tlizumab infusion, well, you can kind of front load that, buy yourself an extra 2.5 years um of time off insulin, hopefully, but also regardless of when you go on insulin, um, there is some exciting data that shows tlizumab still seems to have activity in terms of helping you have an easier form of type 1, because C-peptide is preserved in these, in these, uh, children and adults as well. Uh, here is our longer term extension follow-up for that same, so that's that same Kaplan-Meyer curve, just drawn out um to 72 months, and you can see that after 923 days, only 22% of the placebo patients did not have type one, but 50% of the delizumab patients did not have type one. So that's, that's uh, in, in my mind a Statistically significant, but also clinically meaningful. When we're talking about a 2.5 year delay on average, yeah, I think that is uh clinically meaningful for me. And that's what got tlizumab or TZL FDA approved to delay stage 3. You do only give it in stage 2 currently. We're of course looking at giving it at different stages, but, you know, from the beginning of the talk when I mentioned, when in stage 2, the immune system is just highly activated, it's a very potent time to intervene. That's when telizumab seems to be the most effective. All right, and then the C-peptide data, this again is showing something that we'll see in another tlizumab trial as well, which is that you just see better C-peptide preservation for everyone who's gotten tlizumab, and that's what's both keeping them off insulin, but it's potentially modulating their diabetes. In the future to be one of those, uh, people with type one who not only has residual microsecretion of C-peptide, but what if you have macro good secretion of C-peptide, we know you'll have better A1Cs, fewer complications, um, and generally, uh, have less severe hypoglycemic events even. All right, so then I'll move to this other study, and this is for a different indication for tlizumab. This is looking at stage 3. So we talked about giving it right before you need insulin. It makes it so you don't go on insulin right away. What if you give it right when someone's diagnosed and started on insulin? It does still have a potent effect on C-peptide, um, and that may lead to approval for that stage soon. So I wanted to review this data from the New England Journal, where we gave 8. And up year olds tuplizumab, uh, within 6 weeks of diagnosis of type 1, starting on insulin at that point, that's stage 3 type 1, and looked at change in C-peptide, and here you can see nicely, C-peptide was better preserved in the touplizumab group than the placebo. Generally, their diabetes looked a little bit easier to control. They had better time and range withtlizumab in the black bars versus placebo in the white bars, so you can see um improved time and range overall, and they generally seem to need less insulin to get those better results. So tlizumab here in black again, needing less insulin per day than placebo here in white. The, it's generally seemed to be effective in all groups, so I'm really interested. I would love us to find better subgroups of who's like the best responder totlizumab or these other immunotherapies, but the good news here is, yeah, everyone seemed to benefit pretty equally, even with different um HLA typing in this study. And adverse effects were just like I had mentioned, um, very similar to prior headaches, GI symptoms, rash, and lymphopenia, rarely cytokine release syndrome, just seen in 1.8% here, and they've been watching to make sure there's no viral reactivation with CMV or EBV. Nothing has been clinically significant to date, but that's something we continue to watch in the talizumab trials. And yeah, no difference between COVID infections in that group. OK, so what's it actually look like? Well, if someone's thinking about tlizumab, they generally come and talk to me. I've been running our delizumab program, um. Yeah, I mentioned it's a 14-day daily IV infusion. It does an increasing dose days 1 through 5, with the same dose given days 5 through 14. We do premedicate. We know, you know, rashes in a third of patients, stomach upset, uh, it's in the high proportion of patients. So we actually give ibuprofen, Benadryl, and Zofran standardly, days 1 through 5. And then we have it optionally days 6 through 14. If they've had any sign of an adverse effect, we'll generally, uh, continue those medicines throughout the 2-week period. We watched the CBC and CMP closely, we're monitoring for lymphopenia or transaminitis, and then, of course, we're watching for a hypersensitivity reaction or cytokine release syndrome. Thankfully, we have not seen that to date. And um patients have tolerated this treatment very well. So we just completed a course last Sunday uh for a young man, and he got a rash and some stomach pain. Lived his normal life, um, didn't need to be monitored in the hospital at all, um, and, you know, the big commitment for them was just finding, you know, 14 days where they could do that in a row, but they were able to do that. They received their talizumab, and hopefully now, you know, he's young. I would love if we can get him years without needing to start insulin, which would be very meaningful for him. All right, so that's everything about tlizumab. Now we're gonna flip back to antibody screening, just so I give you some takeaway points, cause I think that's probably the most clinically relevant for everyone here. All right. Here is some consensus guidance from um the ADA. It's a complicated chart, but it basically goes in the detail about who should be checking antibodies, and what do you do if they're positive. I think on this next slide, um, it's a little bit more clear in terms of where in the future, they're hoping this kind of shared antibody testing, um, breaks down. And so this arrow over here, it starts out as primary care, and progresses to subspecialty care. And the basic idea is that we're likely gonna move to a point where initial screening is done. in a pediatrician's office, in a general practitioner's office, we're going to have this as part of, you know, a standard. Again, with other routine testing, like, are we going to be doing lead in this test? Are we're gonna be doing a lipid panel in this test? Quite possibly. We're not there yet, but that's, that's where excitement and where that's where people are moving towards. Right now, of course, we're just talking family members of type one or strong autoimmunity. So, um, Generally, it will look like getting that antibody testing done. If they've got a persistently positive single antibody, we're just watching that over time. If they've got zero antibodies, likely we don't need to screen them again, in my opinion. Some people say to repeat in a few years, but right now, I'm not repeating those. And then if they got 2 or more, that's the life-changing diagnosis. So, How that then shakes out, just to have it in clearer text. If they've got one type 1 antibody, yeah, it's a gray area. We should likely repeat it at some point and see if they go down to 0 or up to 2. Sometimes we're seeing those kids in our endo clinics, but I say may consider a non-urgent endo referral. Often I'm just repeating them, and then they've reverted to zero antibodies cause 50% do, and that's great, but then they definitely don't need an endocrinologist. So, I'd love to give you like very clear guidance for one antibody, but I just have to be upfront. We're in a gray area with what you do with one antibody. I can tell you've got 0, you're low risk, and if you're 2, you're very high risk. One antibodies are still tough, um, but if you just repeat that over time, often it, uh, reverts to 0. Now, let's say you repeat it, or your initial test shows 2 or more, we absolutely want to see those people in diabetes clinic. They have they have type 1 diabetes, but they're like, they're at stage 1 or stage 2. So we need to see them, we'll give them education, we'll give them glucometer, ketone teaching, we'll talk about insulin. If they're appropriate, we'll talk about uh tlizumab therapy, which is for ages 8 and up, and, you know, in that stage 2 currently. If they're in stage 2, and, you know, we have a blood sugar and A1C that's, that's elevated, well, yes, we want to see them, but we want to see them actually, you know, urgently, so within a month, so that we can talk more about deblizumab and get them meter and ketone testing so that hopefully they don't go into DKA. And then, of course, anyone with classic stage three, that's the time we've made all of our type one diabetes diagnoses to date, you know, A1C greater than 6.5, symptomatic with blood sugars over 200. Nothing has changed there, we just need to get them in urgently, um, typically for an inpatient admission, but sometimes as an outpatient admission, but, you know, still same referral pathway for that. But uh yeah, what we're adding now is catching these stage ones and stage twos. All right. So here's our conclusions. Hopefully you've learned about type 1 diabetes staging. Everyone was used to be stage 3, but now we're catching early at stage 1 and stage 2. The antibody screening is important now, it'll continue to be more important, and yes, if you've got 2 or more, you have a 100% lifetime risk of type 1 about. Uh, we've got some new immunotherapies coming, but really right now, our main one is tlizumab. That's the only FDA approved therapy. It's for stage 2, type 1 in ages 8+. Uh, but we're gonna be looking at even using tlizumab at younger ages and for stage 3, which hopefully will come in the next few years. All right, thank you everybody for your time, and I did have some time at the end. I saved some. So if you've got questions about antibodies, like the practicality of sending it, I'm happy to answer anything like that or other questions. Thank you. That was an excellent talk. We really appreciate it. Um, I'm gonna pull up the slides so that everyone can see the code for today. If you have questions, feel free to unmute as well as put them in the chats and we'll leave that time for you guys now. Yeah, Doctor Galgani, great question. Age of onset of type one, yeah, there's There's increasing recognition that it occurs throughout the lifetime. I mean, historically this has all been a pediatric diagnosis or, you know, majority of pediatric diagnosis, but yeah, there's there's now some data even saying about up to 50% of type 1s are diagnosed after age 21. Anybody screening in adults, I think it's more complicated than children. Um, I'm typically reserving recommendations for that for someone who has already, you know, dysglycemia or abnormal blood sugars, or strong autoimmunity. Um, but I don't think we'll move towards general screening for adults, in part because Uh, it's, it's, it is, it is still lower yield in my mind, um, but yeah, I, I agree that you type one can happen at any point. I still think the, the most appropriate focus is on, is on children, where they bear the highest rate of diagnosis and the highest burden of disease in terms of a lifetime with type 1, which, yes, type 1 is unfortunate at any point, but Uh, the good news, like when we looked at that honeymoon data and that C-peptide data, thankfully, the older you are when you're diagnosed, potentially your type one is a little bit different. We're looking a lot more into like the different, um, phenotypes of type one, and unfortunately, the younger you're diagnosed with type one, it does seem to be a little bit more of a severe disease. All right, great question from Doctor Connolly, the cost of therapy. Yeah, so this is, this is an extremely expensive medicine. Um, That being said, insurance coverage has been excellent for it. So every, you know, the, I've gone through insurance approval for several people and it's always been very reasonably uh covered. So all the major um insurance companies have clear criteria for For meeting the criteria fortlizumab approval and infusion, and as long as you, we meet those criteria, which I make sure we meet those criteria, um, they're covering these infusions very well. So, um, yeah, cost hasn't actually limited my ability to infuse yet. It's purely the Actual infusion that's limiting my ability to infuse, cause it's, it's, it is a, it's a lot to sign up for. And then, yeah, Doctor Galgani, yep, pre-diabetes or abnormal A1Cs, that's that group they're, yeah, they are recommending to get antibody screening to make sure we're not calling it pre-diabetes or type 2 diabetes, when really it's latent autoimmune diabetes. All right. And yeah, so Doctor Hill, a young child is negative for antibodies, and I don't need to screen again. I would agree with that statement. And currently, That's my practice. That is a very reasonable and normal practice. There are some groups that, you know, that think repeating in 3 years for high-risk individuals, meaning family member with type 1 is the highest risk, um, that there could be some utility for that. And there will likely be some guidance coming where we screen at 1 to 3 time points in a child's life. That's, that's nothing official yet, and I feel like, um, in my mind, I would take those 0 antibodies and say, yep, you're low risk. I can't eliminate your, I can never tell you there's a 100% chance that it won't happen, but I would take that, put them in that low risk category, and right now I'm not repeating after you get a 0, a negative antibody test.
