Okay, so I'd like to go ahead and get us started off. My name is Dr. Linda D'Ameglio, I'm a professor of pediatrics at Indiana University School of Medicine and the division chief there and a type 1 diabetes researcher in a lot of my day jobs. It's my great pleasure to be invited by the Endocrine Society and the organizers to work with my esteemed colleagues whom I will introduce briefly now and then again as they start to speak to do this session on the topic advances and delaying the onset of type 1 diabetes, what do you need to know now and in the future. So up here with me on stage is Dr. Marion Rewers, Dr. Anna Katsidie, and Dr. Rita Viola. And actually the next slide will have everybody's pictures if I go forward, but it's not advancing there guys, so can you help me? It's advancing on the presenter view but not on the other, okay there. So the learning objectives today is to be able to advise clinical colleagues in the appropriate screening for type 1 diabetes and their patients, to describe immunotherapeutic approaches to delaying clinical type 1 diabetes to patients and families, and to be able to utilize approved immunotherapy to delay onset of diabetes. So the agenda for the next 90 minutes, I'm giving you the introduction and housekeeping, then Dr. Rewers will talk about screening for type 1 diabetes, Dr. Viola speaking about a new era, applying current knowledge. We're going to take a break for a brief panel discussion. I have a couple scripted questions, but if you guys have questions you can use the app, we'll show you the QR code to be able to ask questions, I'll see them and we can bring them in. And then Dr. Katsidie is going to speak of a change of course using immunotherapies to delay the onset of diabetes, and then we'll have questions from the audience again either through the app or we're a small enough group that people can ask them from there. So I'm just going to move forward to say that there's a doc matter discussion board available I was actually not aware of doc matter, even though I am an endocrine society member. I went back and I searched my email, I'm like, oh, I do get emails about it. So there we posted a question a few days ago about a 30-year-old woman with Graves' disease who was well controlled and methimazole, referred with questions about screening herself and her family members for type 1 diabetes. There was a good discussion from the audience and the consensus there overall was not to screen. There were a few people who advocated for it. You can navigate there and look for it. Even if you're not an endocrine society member, you can still go to doc matter and you can participate in discussions and take a look at it there. And then we'll ask you at the end of this as well to kind of think about going there and adding to that discussion. And we'll be moderating it, the group up here and answering things there too. Okay. So with that, I am right on time, I think done with the introductory piece. And so I will turn things over to Dr. Rewers. So Dr. Marion Rewers is the Executive Director and Professor of Pediatrics at the Barbara Davis Center at the University of Colorado. And he was going to speak to us about screening for type 1 diabetes. Thank you, Dr. Rewers. Thank you, Linda. Good morning. I hope your breakfast was nutritious and the coffee was strong because we are going to cover a lot of ground today. And if I may have my first slide. Screening for type 1 diabetes, the pre-symptomatic phase of type 1, has been going on for many years in this country, mostly through trial net and inviting first or second degree relatives of people who already have type 1. So families with knowledge of type 1 diabetes, it's going very well, but if you approach somebody who does not have a relative with type 1 in their family, with the idea of screening for type 1, you may get some of those concerns or misconceptions. And same goes for the providers who see mostly type 2 or endocrine patients. So nobody in my family has it, why should I worry about type 1 diabetes? Well, 90% of cases of newly diagnosed patients, both kids and adults, fall in this category. No family history. It's, you know, I'm dealing with mostly Hispanic population. It's type 1 doesn't happen in Hispanics or African-Americans. Not true. The rates are just slightly lower than in non-Hispanic whites. This is what we get from moms and dads of kids we want to screen. My kid is really active, lean, the whole family is active. Why should I worry about diabetes? Because there's so much misconception about type 1 versus type 2. You say diabetes, people immediately think type 2. Even teenagers and young adults, we don't have to screen because they don't present they're sick and they have symptoms for a long time before we diagnose. It's usually true, but not always. We've seen a lot of DKAs in young adults as well. And finally, what is the best test to screen for type 1 diabetes? Is it OGTT? Most people would have different opinions about this. The PCP ordered OGTT because he heard about impaired glucose tolerance and all of that stuff. But the first available appointment in his system was in 10 days and before the kid had the chance to have OGTT, he came down with DKA. And it is a real case. I saw this patient, the mom was a nurse in Kaiser Permanente, and the DKA was not very severe. But A1C was more than 13%, which suggests that this kid has had symptoms for quite a long time, maybe three, six months. So we ran the antibodies and they were positive, three antibodies in this case, and made diagnosis of not only type 1 diabetes, but type 1A or autoimmune form of type 1 diabetes. So now with this hindsight, what do you think the PCP should have ordered? We'll come back to this question. Our main goal in situations like this is to prevent DKA. And unfortunately, we are doing a lousy job with this. When you look at the numbers, and those are data from Colorado, but it's confirmed by search, which is multistate study, it's confirmed by other local studies, the rates of DKA in the U.S. have been creeping up for the past two decades, and increased from about 30% of kids to now about 60% of kids are diagnosed with DKA. It's not good. Why? Because there is a lot that can go wrong. First of all, it's acute. You've seen DKA, so I'm not going to dwell on this, but it's an acute crisis. And it can cause, in 50% of cases, it causes brain edema, and may cause chronic neurocognitive deficits. There is significant cost to the family, to the society, especially if the kid needs PQ admission. There is a significant psychological trauma to the whole family. And also, very importantly, kids who are diagnosed in the picture of DKA do much worse in terms of their A1C for years to come. Here are our data from the Barbara Davies Center in Denver, showing that those three lines represent different situations at diagnosis. The lowest line shows A1C up to 15 years after diagnosis in kids who were diagnosed without DKA. The middle line, those like this African-American boy who were diagnosed with mild to moderate DKA. And the red line shows the average A1C over the years in those who were diagnosed in severe DKA. So there's a dose-effect response here. And you can extrapolate using DCC EDIC data what the difference of what 0.4% of A1C means in terms of future risk of retinopathy, nephropathy, et cetera. And this is all adjusted for all potential confounders like ethnicity, family history of diabetes, even pump treatment, access to care. So it's real, and it has been confirmed by studies in Europe. Search also confirms the observation. So we really want to accomplish two things. No DKA if possible, no hospitalization, and the lowest A1C possible at diagnosis to preserve as much insulin-producing cells as possible for the future cause of diabetes. You've seen this slide probably many times. It's the current ADA, ENDO, and JDRF-supported staging of type 1 diabetes. Now we know that type 1 diabetes starts on average 5 to 10 years before clinical onset, before we have those symptoms, as an autoimmune disease. Initially, there are no problems with sugar, normal glycemia, and then closer to clinical diagnosis, on average two years, patients experience dysglycemia defined by A1C above 5.6 and fasting, impaired fasting glucose, impaired glucose tolerance by OGTT. We are working on adding CGM criteria to this definition of dysglycemia, but it's not there yet. And then stage 3, this is what we used to call newly diagnosed diabetes. Now there have been multiple studies following kids over years for different purposes to find out the causes of type 1 diabetes, environmental causes, genetic causes, and they are listed at the top of this table. Those studies observed something interesting, that if you screen for antibodies and follow and then do a little bit of education and monitoring for those kids who are antibody positive, the rates of DKA diagnosis are very low, about 5%. And this is one quarter of what you see in Europe, in the general population, where the rates are generally between 20 and 30%, and obviously much, much lower than what you see in the United States at the bottom of this slide where the rates are between 40 and 60%. Now there are two studies that have been around long enough screening kids from the general population and doing the same type of monitoring education follow-up, FRIDA in Germany and ASK in Colorado, and amazingly they also found those studies that you can prevent DKA in the general population, not only in the relatives of people, kids who have been screened for genetic risk for type 1 diabetes. So there's a hope we can do much, much better if the screening becomes widely available. So who should be screened? Currently the ADA recommends at the top of the slide that we screen people with a family member, first, second degree, regardless if they want to participate in trial net or not, because there's a clear benefit. Also kids who participate in the research studies like ASK or FRIDA that I showed before, kids who for whatever reason got a genetic test and somebody tells them your child's GRS, genetic risk score, is high, maybe 1 in 10 of those kids will develop diabetes. So this is already in the ADA recommendations, clinical standards of care. What is clinically appropriate or at least acceptable in terms of clinical decision-making is to extend the screening already now to people who have other autoimmune conditions like celiac disease, autoimmune thyroid disease, maybe Addison's. So they are at much higher risk of developing type 1 diabetes as well, similar risk to that among relatives. And finally, what we are working on in many centers across the U.S. and the world is to provide strong evidence enough to extend the screening to all kids and adolescents and probably most of the adults. Why? Because it turns out that adults have the same prevalence, the same frequency of antibodies as the kids. So here are programs that are currently available in the U.S. that screen people for type 1 diabetes. I mentioned TrialNet. You know it very well. Then ASK and ASK the Experts, respectively in Colorado, and ASK the Experts is available all over the U.S. T1Detect, advertised by JDRF on their website. Those programs don't require PCP or endo-recommendations or referral. They are research projects widely available. And finally, there are some very recent programs in Virginia, Midwest, and the state of Washington listed at the bottom of the slide, which start from genetic screening in early childhood, usually newborns, and then they presume that those kids with higher genetic risk can be followed, identified, found later on for antibody screening. I'm personally very skeptical of this approach because it's been tried by Primit in Virginia. It just doesn't work very well in the U.S. People cannot be found in our health care system. They are lost and you can expect a very poor performance of such an approach. Okay, so what do we use to test for pre-symptomatic diabetes? Of course, autoantibodies, islet autoantibodies. And this particular study gave the foundation for the current staging because it's pretty clear that if somebody has two or three autoantibodies, there's probably 100% lifetime risk of progressing to clinical diabetes. However, the problems that we are still struggling a little bit with is what to do with people, both kids and adults, who are found on screening to be positive for only one antibody. If you combine all of them in one category, their risk is not very impressive, about 15 to 20% lifetime. But there are already new methods I will mention later to tell the difference between those truly at risk and those not at risk at all among people with one or two antibodies. It is a big problem because if you go to the general population, 83% of all people identified as positive are positive for only one antibody. So, you cannot ignore it. You cannot say it doesn't exist. We don't know what to do. It has to be addressed heads-on and we are doing this as we speak. So, here are the tests and laboratories that are available in our country to do the screening. Radiobinding assays are still kind of gold standard. Also, there are many limitations and probably those assays will go away in the next few years. ELISA-based assays are relatively cheap and relatively accessible through Quest LabCorp, but their performance is not so great, especially for insulin autoantibodies. There is no good assay for insulin autoantibodies in the ELISA class and it is the most important autoantibody in early childhood. Early means up to the age of 10. Then, ECL assays developed in our center, they are great. They are the best assays currently available according to the international standardization program called IASP, but they are available only in a limited amount in limited locations. And the ADAP offered by Enable Biosciences and JDRF to undetect, it's relatively easy to get if you follow the instructions on the JDRF website, but we have very mixed results in terms of confirming those those positive antibodies. In that particular program, about half of positives are not confirmed on a natural test. So, there's no golden solution yet, but at least there are some options. In Colorado, in the ASK study, we start screening, general population screening, and we've screened 33,000 kids already. We start from 5-Plex ECL assay, which is cheap, high throughput, and includes also transcutaneous autoantibodies, so we screen also for celiac disease. Then, any positives are called back for confirmation at the BDC, and we followed them, confirmed the monitor, tried to prevent the DKA, and, of course, offer participation in trial net in other intervention studies. And now, for stage two, we have teplizumab approved, so it can be given not on a research basis, but as a clinical intervention. What age should we screen kids for allelotoantibodies to make it reasonable for providers? It's a busy slide. On the left-hand side, you see results of statistical modeling. I'm not going to go there, but the highlighted row shows the best combination. If you have two shots during childhood, you should screen first around the age of two, maybe between one and three, and then repeat it around the age of six, about two to four years later. And if you are dealing with a kid who is already eight or ten, it's not too late. All children should be screened regardless of age. Cost-effective analysis. To make a long story short, the screening that ASK is doing is already cost-effective because it prevents so much DKA and, by extension, provides kids with a better future using the A1C as the milestone. So, our hints for extension of general population screening. The initial screening has to be sensitive and disease-specific. There has to be a confirmation of all positives using the most specific assay. We cannot ignore single autoantibody positive people, and the multiplex assays may be the future for low-cost, high DKA benefit programs. But there are many questions listed here about around the assays that are available, only available in limited amount, about genetic press screening, about cost-benefit of screening, especially among adults, and finally, what effect on our cost-benefit analysis will the availability of teflizumab and similar drugs in the future have. This is the second patient that I wanted to show you. A three-year-old girl who attended, should I read it? Yeah, okay, who attended a world child visit with her mom. Mom has autoimmune thyroid disease and it runs in her family. The kid is perfectly healthy, normal development, no meds, no past medical history, normal physical. So, the only question mom has, you know, should I get my kid screened for thyroid disease and maybe other autoimmune diseases like type 1? I saw this movie on TV about type 1 yesterday. So, the PCP reluctantly sends the blood for screening and the kid turns out to be positive for two autoantibodies, to insulin and to GAD. So, now please look at your screens, at your phones, and answer the question, if this child were negative on screening, what would you do next? Would you screen this kid again ever? In one year? Maybe in two to four years? Or wait until the kid is kind of now entering young adulthood and check just in case if there are antibodies at that point. Okay, I guess we get the picture, which, yeah, you can continue. It takes us to the last of my slides. To wrap it all up, type 1 starts many years before what we call clinical onset. About half percent of 1 in 200 of kids in the U.S. have already multiple allele autoantibodies, or stage 1 type 1. Eighty-four percent of those kids who are screening detected don't have any relatives with type 1. And we should, if possible, screen first at 2 years of age, then 6, and then at 10. Screening for autoantibodies and monitoring can prevent more than 90% of DKAs that we are seeing, and it should become routine in the near future because it appears to be cost-effective. Thank you so much for your attention. Thanks, Marian, for an excellent talk and an excellent introduction. And I'm just going to note, because I don't know that it was completely clear, so there'll be a question at the beginning of each section that you will not see the results to initially, but you will then see, we'll go over them at the end. So, like that first question about the screening test for the 14-year-old that Marian presented, we'll come back to at the end. You'll get to answer the question again, and then we'll show you guys the results. For those who are new to the room too, your QR codes for the questions are on your table. So, please, there'll be a poll question coming up, so please continue to engage with us in that way. So, with that, I will not take any additional time from our next speaker, who's Dr. Viola. She is a professor of pediatrics in the Department of Pediatrics at the University of Oulu in the Oulu University Hospital in Oulu, Finland, and she's going to be speaking to us today on a new era, applying current knowledge to prevent type 1 diabetes. Dr. Viola. Thank you very much. So, I start with genetics. So, we all know that genetic factors increase the risk of type 1 diabetes also in individuals who are screened positive for islet autoantibodies. So, there is strong genetic background behind this disease, and we know that positive family history is one of those genetically determined characters, so particularly if there is a first degree relative with the disease. But also, what we have learned already many decades ago is that there is one gene region, which is class 2 HLA region in chromosome 6P, which is a very strong and still the strongest single gene region that confers increased risk to T1D. And I've just listed here the class 2 genotypes. They are DR4, DQ8 genotypes, and of note, there are also protective, strongly protective genotypes within this gene region. But this genotyping has been used mostly in a research setting. So, the field has developed very much during the last years, and we now talk about genetic risk score, and that is built from approximately 60 genetic markers. So, we have learned that there are other genes that contribute to the genetic risk, and there are now programs that test the individuals for all these markers and can give a risk score. And then, on top of that, if clinical characters such as family history, age, and insulin autoantibodies are added, we talk about combined risk score, and this is where we are in this field in terms of prediction. So, we have an individual, and this is from the same cohort that Marian just showed, a little bit different graph. In the starting point, we have an individual positive for multiple islet autoantibodies. So, over the next 15 to 20 years, the risk approach is 100% to really be diagnosed with clinical disease, and this was a great collaboration between three prospective studies from Finland, Colorado, and Germany. So, why does this disease develop? So, there is a lot of research on immunological factors behind the disease, and particularly the T-cell role in development of T1D. And here, the green fields or boxes are showing evidence for the T-cell involvement in development of the disease. And of course, the islet autoantibodies are a kind of clear sign that there is something to do with our immune system, and the current view is that CD4 positive T-cells are first activated, and then in the end of the process, it is actually CD8 positive T-cells that are the final mediators of beta cell destruction. And now, there is still a kind of discussion and debate for and against the primary pathogenic role of T-cells in human T1D. So, are T-cells the primary mediators? So, there are studies about genetics. Again, green boxes are speaking for the role of T-cells being the primary mediators. Then, there is some functional evidence, so from samples taken from human beings, but also from experimental animals. And as you see, the red boxes are there too, so the evidence is not so clear. So, there are arguments also against the primary pathogenic role of T-cells. And then, some histopathological evidence is very important. You may know about the input effort where pancreatic tissue samples can be studied from donors who have been deceased and who have given permission to study their pancreatic tissue. Again, both evidence for and against the primary role of T-cells. And then, clinically, the evidence is mostly for the role of T-cells. So, this is where we are about in our current understanding of the role of pathogenesis of type 1 diabetes. So, which are the options to treat or prevent type 1 diabetes? So, on the left-hand side, you see the disease process, kind of predisposing factors, unhealthy beta cell, dysfunctional immune system, then metabolic derangements. And when the disease is there, there is a risk of complications and higher mortality or decreased lifespan is a fact too. But on the right-hand side, there are the options that we are investigating at the moment and which are there on the table. So, on the upper box, we could use antigen-specific therapy, so kind of tolerate our immune system against beta cell antigens. We could introduce some medication relieving the stress that is present in the pancreatic beta cells or stimulate the remaining beta cell mass. Then, the white box in the middle, we could use systemic approaches. So, we could give targeted immune medulation or immune suppression, and that has been tried, immune suppressive treatment since the 80s. And some studies investigate T-regulatory cell expansion to help the immune system to tolerate better. Then, the blue box is addressing complications, which is, of course, what we all do, treat T1D as well as possible. And the green box down there is, there is also a possibility and strong research on a possibility of curative treatments by beta cell replacement therapy. So, I go back to the very same case description, the three-year-old girl Marian just described us. It's the very same information here, so I don't read through. So, this girl, three-year-old, only was detected to be positive for insulin antibodies and GAT-65 antibodies. Now, the question comes here, and you can now take a look at your cell phones and answer, which of the following tests are the family and their PCP most likely to use in monitoring this child for dysglycemia? Okay, still some people submitting their answers. I think we are done. So we come back to the answers later. So the question is here, why monitor people who are positive for islet autoantibodies? So what we can do by monitoring is that we can see and we can detect when stage 3 type 1 diabetes is approaching. So prediction of timing of stage 3 is important, particularly to the family. And they ask this question many times, when my child will develop T1D. Then, as Marion mentioned, prevention of DKA. And then by knowing and detecting the diagnosis early, it allows start of insulin therapy also early. And with very small doses, which are, of course, individual and then can be increased gradually. And this is a clear benefit also to the family so that they have time to learn the treatment in peace and not start from the intensive care unit with DKA. And then we do have a possibility to delay stage 3 type 1 diabetes with approved therapy. You know about this Teblizumab anti-CD3 monoclonal antibody that is now available here in the US. And even if we wouldn't have possibility to that therapy, there is another possibility to participate in prevention and intervention trials, which are many ongoing to find even a better way to delay or perhaps even prevent. So there are clear reasons for monitoring and how to do this monitoring. So there are several options. We can offer a glucometer and families can have that one at home and measure blood glucose values regularly or in case of acute sickness and so on. We can follow hemoglobin A1C. We can measure random plasma glucose in the clinic. We can perform oral glucose tolerance tests, which is at the moment the gold standard for dysglycemia and also for T1D. And now we have this great tool in patient treatment, CGM, and that is also available for us. But we are not yet there that we would have clear definitions, which is dysglycemia, which is stage 3 defined by CGM. And then, of course, we can monitor islet autoantibodies. So it is important to confirm if you have a one sample positivity, because if it's a low titer islet autoantibody, these are often transient. And if single antibody positivity is detected and then also confirmed, it's still a matter of follow up, particularly during the first years after that point. Because the single positivity can remain stable or it can revert to negativity or spread to multi positivity. And these pathways happen most likely during the first two to three years after the detection of single positivity. So early diagnosis is very important and monitoring before that also has a clear benefit. This is from a Swedish study and now we have hemoglobin A1C levels in the dotted line. You see clearly higher among those diagnosed individuals who were not followed up or monitored before diagnosis compared to those who were monitored before diagnosis. And then, of course, later. And this is from our study from Finland, the prevention of diabetic ketoacidosis. So we end up with an incidence of only five percent by this monitoring and we almost get rid of severe diabetic ketoacidosis when we have monitored these children. And then this hemoglobin A1C is also something that we have clear evidence that it's a very simple tool. And by following hemoglobin A1C, we can predict time to diagnosis. So all these children in this graph, more than 400, were multi positive and they were regularly followed for hemoglobin A1C. And you can see that they're one to two years before diagnosis, which is this zero point. Zero point is diagnosis. So looking back from diagnosis, you can see a subtle increase of hemoglobin A1C already one to two years before the diagnosis is there. So you can and the white boxes are those who didn't show any increase in hemoglobin A1C and were not diagnosed within the follow up of this study. And how much hemoglobin A1C should rise to be significant? So in the graph, A graph on the left hand side, upper left hand side, it's if you only have information about multiple autoantibodies. So the median time to diagnosis is about seven years. Then panel B on the right right hand side, if you have detected 10 percent rise in hemoglobin A1C, say from 5 percent to 5.5 percent, the probability to develop or the median time to stage three is only one point one year. And panel C down there, if you have 10 percent rise and an additional rise on top of that, then it's less than one year. That is the prediction to stage three. And you can also use absolute numbers, such like 5.9 percent and so on. And OTT and random plasma glucose are also predicting the time. So it's it's here in the middle where you have the two hour plasma glucose value. And it also starts to increase about one to two years before clinical diagnosis. And on the very right hand side, you have just random plasma glucose, non fasting plasma glucose measured in any clinic visit. And it's also quite predictive. So I think this is remarkable. And if you look at the left left hand side panel, that is fasting plasma glucose, which comes late. So like about six months before diagnosis, it's not so good in predicting childhood type one diabetes timing. We also have studied CDM parameters and we have detected in this very small series of children. So the black dots are those who are multi positive for islet autoantibodies and the white dots are autoantibody negative controls. Both groups being HLA at increased HLA risk. And you can see that the black dots, the multi positive individuals have clearly higher variation in their CDM glucose values. But compared to the to the autoantibody negative controls. But there is a wide range where the values vary. And later we performed a study when we put CDM and performed OTTT simultaneously. And we selected individuals from all these stages of type one diabetes. And you can see that that CDM glucose values very nicely go together with the stages. So you can detect higher sensor glucose values in stage three and also in stage two. But we are at the moment we are in the situation that there is no consensus about the cut of values and which of the CDM parameters is the best to diagnose. For example, stage two. So you will hear about this more. So I predict that CDM will become a very, very popular tool in the future. Okay, so and this is my opinion. So CDM can be used for monitoring when you have experience and when it's available. But it's interpretation may not be straightforward. It gives you a lot of information and the family asks a lot of questions. And you may have difficulties to answer to all those questions. And it's not included currently in the diagnostic criteria of stage three T1D. So we need more evidence. So here are my key points. So when you detect positivity, you must confirm the positivity for a single or multiple islet autoantibodies. And if it's a single positivity, that requires monitoring also for islet autoantibodies for the two to three initial years to detect if the person converts multipositive. And then remember this, that positive family history or presence of T1D risk genes, or if there is a high GRS or CRS risk score available, that increases risk of T1D in autoantibody positive individuals. And you should monitor glucose metabolism in autoantibody positive individuals every six to 12 months to predict timing of stage three, to prevent DKA, to detect stage two type one diabetes. And now immunotherapy or participation in an interventional prevention trial is possible for patients in whom stage two T1D is detected. Thank you. Thank you. Thanks to both of our initial speakers. We're just going to pause for a moment here. And I'm going to go forward to the next slide. For a brief panel discussion, I'll tell you that we're getting some good questions in the chat. So please submit those. And I'm trying to make sure we have time for them at the end. But for now, I have a couple scripted questions that I will ask our panelists. I'll ask you to try to keep your answers to about 60 to 90 seconds, although they're interesting questions. So the first question I'll ask, the first person who's not yet spoken this morning, is Dr. Sidié as an adult endocrinologist. When might you consider using continuous glucose monitoring for monitoring in somebody with antibodies? We've heard a pediatric endocrinologist perspective. What is yours as an adult endo? Thanks, Linda. I think it would be useful if there's a decision to be made. And I think that there'd be a conversation with a patient in terms of what are they willing to do. I mean, I think definitely getting A1Cs, doing self-monitoring of blood glucose are options. But there are patients who either won't do it or can't do it. And in those patients, using a continuous glucose monitor, I would say periodically. I'm not sure I would have somebody wear it all the time to gather more data. Particularly if one senses that the risk is higher for whatever reason, younger age, more antibodies present, and you think that there will be more data to gather, it could be offered. There are lots of people who just don't want to wear a CGM. And so I think it would be a shared decision making. And then finally, at least in our country, it's a matter of whether insurance would cover it or not. Some are very strict about when they would cover such a device. And of course, all of this, as we heard just now, there are actually no guidelines. So a finding on a CGM that is concerning would necessitate a follow-up A1C oral glucose tolerance test. Yeah, I agree. And that shared decision. And then even for the people that are insured, the out-of-pocket cost for something. So that's why the guidances and guidance and guidelines are important. Amari, I'm going to turn to you for a moment to just tell us an example of a question that either a patient or study participant has asked you about ways to prevent type 1 diabetes. We've talked a lot about screening. What are some questions that you get from people in your studies? So the first question is, is it going to be a pill, maybe shot? Nobody wants infusions, at least initially. So this is a tough sell. But the first choice would be diet, especially moms say, can I do it by myself? Can I add vitamin D, omega fatty acids, maybe less carbs, less calories? This is what they would prefer to do it on their own. If it has to be a doctor or clinical trial, then they have follow-up questions. Is it going to take just one week up front or maybe one month or years? Or do I have to take it for life? And now kids have very different questions. And if you ask them the right way, you may be surprised. They worry about, can I play my sport, my favorite sport? Can I play soccer while having this intervention? Can I eat burritos? Because somebody told me I won't be able to eat burritos. And finally, will this intervention you are talking about make me different? Can my friends see that I'm taking something, like I'm going bald, for example? So those are the type of questions. Of course, when we get more into what the intervention really is, the parents start asking about side effects. What are the short-term side effects? And what are the potential long-term side effects, like cancer? And it's not unreasonable because, you know, checkpoint inhibitors and cancer treatment can cause diabetes. Some of the immunomodulators that we use to prevent type 1 diabetes may cause cancer. So those are the types of questions we are hearing. Those are good discussions. I also find that sometimes people conflate or confuse immunomodulation and immunosuppression, and some immunomodulators immunosuppressive. So that's another thing to consider as you're having these conversations. And then, just briefly for Rita, how do you describe antibody positivity? So Marion talked a lot about all these different antibodies. How do you describe it to people you see who screen positive? Yeah, it's usually bad news to the family or to the individual. So you need to pay attention to the communication and use enough time. And what I tell, I obviously work with young children and their families, that these antibodies are now there. If it's the first sample, I say that we have to confirm this just to be sure. But if it's true and the antibodies are confirmed, then it's a sign that the disease process is ongoing behind there without any symptoms. And the antibodies themselves are not considered harmful, but they just reflect the immune process that is ongoing in the pancreas. And what we know about the significance of these antibodies is, unfortunately, that they are very predictive to the clinical disease. We just don't know when, because it varies a lot between individuals. So the shortest time I've seen, it's just a couple of months from detection of islet autoimmunity when the diagnosis is there. And the longest time, more than 25 years. So it really varies between individuals. But how we can then predict and answer to the question when it's coming is to monitor, for example, hemoglobin A1C. So that's really helpful. Yeah, I think it's always a tricky conversation because the idea of risk is a risk initially going into the screening test, and then there's that risk perception coming out of the screening test. And it's just it's a tough discussion. We're grateful to this group of people, and many people in the room have contributed to the knowledge that gives us the ability to give people a better idea of their risk. But it's hard because it's very uncertain. OK, so with that, we have some good questions in the chat. Continue to add to it and upvote them. If you see ones in there you want to see answered, I will say that the first one, which is getting the most upvotes, is asking in part about which antibodies are most aggressive. And that, I think, Rita answered a little bit right now in her question, which said the antibodies themselves are not pathogenic. But we will get to which antibodies are most worrisome to us at the end in the open discussion. So please continue to submit questions. And with that, I will turn things over to our last speaker. Dr. Sidday is the program director of Endocrinology and Metabolism Fellowship Program and associate professor of medicine at Johns Hopkins in Baltimore, Maryland. And he'll be speaking to us about a change, of course, using immunotherapies to delay the onset of type one diabetes. Thank you, Linda, and to the organizers for inviting us to give this presentation. So this presentation is obviously about this patient that I'm going to present, a patient who is in stage two of type one diabetes. This is a real case that presented to our group. An 18-year-old white male with fatigue, low libido, memory loss, and no morning erections presented to an internist. There was one year of weight loss, but it was intentional and was about 13.6 kilograms. There was no polyurea or polydipsia. The physical exam was non-focal. And you can see that the BMI after all this weight loss was 31. Initial labs showed a total testosterone of 437 nanogram per deciliter. A TSH was normal. The family history was notable for a paternal grandfather with type two diabetes mellitus. And multiple persons in the families had Hashimoto's disease and rheumatoid arthritis. So this good internist referred the patient to a urologist who ordered the following labs. A random glucose was 104 milligram per deciliter, and A1C was 5.7%. The total testosterone was 337, and a prolactin was elevated at 12 nanogram per ml. The patient was then referred, finally, to an endocrinologist. So the endocrinologist repeated some of the workup and showed the fasting glucose at 95 milligram per deciliter, which is normal. Hemoglobin A1C was again abnormal at 5.8%, and GAD antibody was positive, and islet cell antibody was positive. So the patient is going to be going away to college in the fall, and the family asks for treatment options that would prevent him from being diagnosed with diabetes. And so the poll question is, what treatment options could you offer this patient to prevent the onset of type one diabetes? There are intranasal insulin, anti-CD80 based treatments, anti-CD3 based treatments, and no approved treatments to offer. Okay, so it sounds like most people would say that there are anti-CD3-based treatments. And I think what we're gonna emphasize here is this subtlety is that the anti-CD3-based treatment that is approved is approved to delay the onset of diabetes. And we're gonna talk about that in a second. So the labeling does not say to prevent diabetes. So of course we have shown this slide before and I put it up here again to remind you that we're now talking about patients that are in stage two of diabetes. That is, they have detectable autoantibodies and there is dysglycemia present. So for these patients, what is there to offer? And there has been a lot of work, as many of you know. And I'll go through these two slides very quickly to suggest to you that, of course, there have been studies at every stage of diabetes to see if there could be prevention of the next stage. So these are all studies that looked at patients at stage zero and the intervention was essentially trying to avoid some potential environmental trigger, either bovine milk protein or bovine insulin, so the insulin was removed from the milk formula, or delayed exposure to gluten. And the primary outcome would be the progression to stage one, and that is the development of autoantibodies. And you can see that the primary result was achieved in many of these trials, that is, delayed or decreased incidence of autoantibody detection, except for in the gluten study, which was negative. Now, what about patients who are in stage one diabetes? There have been several trials looking at this. They include interventions such as nicotinamide, which can serve as a scavenger of free radicals, increase NAD plus levels, and is hypothesized to help target cells protect themselves from autoimmune attack. And there is the administration of insulin, either by oral route or other routes. This would be to induce tolerance to a self-antigen. And abatacept, which is a molecule that binds to CD80 or 86 on antigen-presenting cells and prevents co-stimulation of T cells. And in all of these, the primary outcome was the time to type one diabetes diagnosis, by which I mean stage three, or the diagnosis of type one diabetes. And you can see that in all these study, the primary outcome was not achieved. So let's talk about stage one and stage two diabetes. And I'm highlighting these three trials. One involved an alum conjugated to glutamic acid decarboxylase. This was a safety study. There's also been parenteral insulin. And the primary outcome was time to type one diabetes. And this also showed no benefit in terms of the primary outcome. And then finally, we have teplizumab, where the primary outcome was time to diagnosis of type one diabetes. And the primary result was that there was a delay in the onset of diagnosis. And so we'll spend the next several slides talking about teplizumab. So these are the two main studies. I'm sure most of you have seen at least the first one. And then there was a second study, which was a follow-up study that was published in Science Translational Medicine. And these two trials formed the basis for the FDA's approval for teplizumab to delay the onset of stage three type one diabetes. In adults and pediatric patients who are eight years or older, and who have stage two diabetes at that time. So first off, what is teplizumab? Teplizumab is a humanized FCR non-binding anti-CD3 antibody, and is a derivative of OKT3. So the picture on the right shows you an antigen-presenting cell on the top and a T-cell on the bottom. And in teal color is the T-cell receptor. And the CD3 molecule is these three dimers that sort of form like this basket or cage below the T-cell receptor. And the CD3 molecule is very important for T-cell receptor signaling. Later on, it was found that OKT3 targets the epsilon chain of CD3. And these two amino acids in the humanized version in the FC region prevent FCR binding and were designed to prevent the cytokine release phenomenon that was a big part of OKT3. So murine studies with anti-CD3 monoclonal antibodies have shown that it may prevent or reverse autoimmune diabetes. So I wanna give a little bit of history. There have been many studies with teplizumab. And I wanna review some of the studies in newly diagnosed patients that suggested PROMIS. So the first of these was published in 2002 by Kevin Herold and his colleagues. And it was a study of about 24 patients who were randomized to a course of teplizumab or just control. And the primary outcome was whether they could arrest the decline in insulin production. And this was measured by the C-peptide response to a mixed meal tolerance test. And in this, the primary outcome was that it did arrest the decline in insulin production for one year. And so versus in the control group, very, very few patients had a stabilization of C-peptide release. Most patients in the C-peptide in the control group actually had a strong decline in C-peptide release. So there were further studies. And I wanna highlight the one that was published in 2011. And this was a much larger study. It was 516 patients. It was multicenter in multiple different countries. And the primary outcome was proportion of patients who achieved an A1C less than 6.5% or insulin use that was less than 0.5 units per kilo. So this was more of a sort of a firm metabolic outcome as opposed to preservation of C-peptide. And in this study, there were two courses of teplizumab given at baseline and at 26 weeks. And this treatment did not show any difference in the proportion of subjects reaching this primary endpoint between placebo. And it turned out they actually tested three different types of teplizumab courses. Now, in sort of exploratory analyses, they did find preservation of C-peptide in a group of patients. So there were responders. And they did show less insulin use but at a particular A1C level. But these primary endpoints were not met. Then there were two other smaller studies that involved two courses of teplizumab. One was ABATE, and it showed that C-peptide responses were preserved for up to two years. And then there was a seven-year follow-up of the ABATE trial, and it showed that there was no longer this preservation of C-peptide responses and that A1Cs and insulin use were no different seven years out from the diagnosis of diabetes. And all of these trials taken together suggested that preservation of C-peptide responses occurred in patients treated with teplizumab. That treating earlier on, soon after the diagnosis of diabetes, seemed to have a positive impact on this response. And there was an impression that younger patients responded more than older patients. So let's talk about this trial, this trial net trial that was done in persons at high risk to develop stage three type one diabetes. So all the previous trials were in newly diagnosed people, so people who already had stage three disease. This trial was a phase two trial, placebo-controlled. As you can see, it took quite a few years to complete. The participants were non-diabetic relatives of persons with type one diabetes. They had to have two or more diabetes-related auto-antibodies detected. And dysglycemia had to be shown on oral glucose tolerance tests, but obviously not to the level of, that we would consider to have stage three diabetes. So just a couple words about this. This was 76 patients that were enrolled. It turns out that 55 of them were less than the age of 18. And 70% or so actually had three auto-antibodies or more detected. To give you a sense of what this patient population was. So the treatment was teplizumab versus saline. This was a 14-day infusion. The doses increase with each successive day. And eventually, there were, it was a two-to-one randomization. And the primary endpoint was time from randomization to diagnosis of type one diabetes at stage three. And so this shows you the primary endpoint results. It shows you the medium time to diagnosis was 48.4 months in the teplizumab group. And 24.4 months in the placebo group. And the hazard ratio for type one diabetes diagnosis in teplizumab versus placebo was 0.41. So the graph shows on the y-axis, the proportion of patients that are free from diabetes. And on the x-axis, the months from randomization. And you can see that by studies end, about 45 or 50% of the teplizumab patients remained free from diabetes. Okay. They did some analyses to answer the question, who are the people that responded to teplizumab? And so although there were only small numbers of patients to do these analyses, they saw that the increased likelihood of response was in patients who had the high-risk HLA-DR4 haplotype and the absence of an HLA-DR3 haplotype, the absence of zinc transporter eight antibody positivity, and a C-peptide response after OGTT that was actually below the median. So now, this study was followed up, as I told you before, in a second paper. The median time of follow-up in this second paper was about 900 plus days, while in the initial trial, it was about 750 days. And so in this trial, you can see that the median time to diagnosis in the teplizumab group was 59.6 months, but in the placebo group was 27.1 months. So this delay in the progression to stage three diabetes was maintained in this longer-term follow-up. Now, the one caveat I will say about this in the interpretation of any of these types of follow-up studies is that the patient numbers become very small towards the end of this follow-up. So what are the potential mechanisms of teplizumab? The exact mechanism by which teplizumab may preserve beta cell function is not known, but in murine studies, it has been observed that it is associated with clearance of immune cells that are infiltrating from the islets. There is induction of self-tolerance. There is increased regulatory T-cell function, as was alluded to before, and it targets effector T-cells. And many of these investigators have actually studied T-cell populations, and they see an increase in so-called exhausted memory T-cells that have reduced secretion of these cytokines, interferon gamma and TNF alpha, for example. So we've talked a lot about what was the results of these trials and the efficacy, and now we should think about some of the adverse effects. So we'll start with a case for this purpose. A 12-year-old sibling of a person with type 1 diabetes was screened by her parents and found to have two positive autoantibodies. This is a case from one of my pediatric colleagues. The child is otherwise healthy without any other medical problems, and workup showed an A1c of 5.9%, which is abnormal fasting glucose of 118 milligram per deciliter, and a two-hour post-oral glucose challenge of 165 milligram per deciliter. So all of these studies suggest dysglycemia. So based on these findings, you assess her to be at high risk of progression to stage 3 type 1 diabetes, and a decision was made to initiate teplizumab. So what should a patient know before selecting or starting teplizumab? And I think these are some of the things that we all will be discussing with these patients. I think it's important to say that there is a medium delay of type 1 diabetes onset. That is, 24 months could be even longer, up to 32 months. In persons who do not respond, insulin may be required, insulin will be required, sorry, but the dose requirements may be less. And there are some practical matters that patients and families should consider. This is a daily intravenous infusion for 14 days. We'll likely need a couple of hours in the infusion center, and there will be a need for ongoing monitoring for side effects and, obviously, for the occurrence of diabetes. And if there is a response, by which I mean to say that type 1 diabetes diagnosis is delayed, the rate at which this is going to, I'll say, use the word, type 1 diabetes will occur later on is not yet known. So what are some of the side effects that patients should be counseled about? So all of the trials have shown rash in about 30 to 40% of patients. This is transient. In some studies, it was described as eczemoid. There's lymphopenia in a very, very large proportion of patients, upwards of 70 to 80%. The nadir of lymphopenia occurs at about five to seven days, and almost all patients in these trials recovered their lymphocyte counts by about day 45 or so. There was only one or two patients who had lymphopenia that persisted out to about two or three months before it recovered completely. And the cytokine release syndrome occurs in about 5% of patients. There are risks for infections and liver injury. So the trials showed that in people, for example, who were serologically positive for EBV, there was an increase in EBV DNA levels. And there were a few patients who actually developed an infectious mononucleosis type of syndrome, but the EBV DNA cleared in all subjects. And the same is true for CMV. Screening for TB is appropriate as well. Okay. So in the same case, this patient actually was referred by my colleagues to receive teplizumab. And on day five after treatment, the patient develops lymphopenia. And so the question that you should ask yourself, and I'm sure the families would ask you, is what to do next and how should you respond? And the answer is you should wait and allow for the lymphocyte counts to resolve. There was in these trials no increased incidence of other infections compared to placebo. I'll just say I've been told by some of my colleagues here that if the rash occurs, there might be a temptation to treat with glucocorticoids and this should not be done because this will dampen the response of the drug that is being given. Okay, what about practical considerations for us as practitioners? And this is how I approach this. I'm primarily a clinician. This is an intravenous infusion daily for 14 days. So for example, the state where I come from, the state of Maryland, there is no infusion center that is open seven days per week. And you have to plan for that. Are there people in your group who have experience with immunotherapy? I think this might be something that is new for a lot of us and we're gonna have to get experienced with it. And there will have to be monitoring for adverse effects and side effects. So in these trials, there was regular monitoring and it would be reasonable to do screening periodically. Of course, there's monitoring for occurrence of stage three type one diabetes. And in the trials, these patients had oral glucose tolerance tests at three months, six months, and then every six months. They had random glucoses that they continued to do every three months. The drug is approved for patients who are at high risk for developing type one diabetes. So those would be two antibodies or more that are positive and dysglycemia. But in the trial that I just mentioned to you, the patients were all first degree relatives of persons with type one diabetes. And the question that we don't know about yet is should we give them a second course? Fortunately, there are trials that have used two courses. They were not in this specific patient population, but there's some information. So I'm gonna quickly go through this slide just to tell you that there are some studies on the horizon that you should keep your eyes out for. So first and foremost is the PROTECT study. This is participants who are younger and have been recently diagnosed with type one diabetes and are positive for one or more islet out of antibodies. There are non-antigen specific immunotherapies that are being done in patients with stage two diabetes. And the one I'll mention that is enrolling right now is low dose antithymosite globulin. This targets multiple T cell antigens. And there's a MAS1 adjuvanted insulin B chain that is in phase one. MAS1 is just a nanoparticle immersion that boosts TH2 responses. And in the interest of time, I'll skip this slide. It simply demonstrates that there have been other immunologic studies and more recently verapamil that have shown some promise in C-peptide preservation in newly diagnosed patients with diabetes. All the things that are circled had those positive effects. And this raises the possibility for combination therapies in the future. So the takeaways are teplizumab is FDA approved to delay the onset of stage three type one diabetes in patients who have stage two type one diabetes and are eight years or older. Practices are currently establishing protocols for infusion and monitoring. And we all should reach out to colleagues who have experience with this. And there are ongoing trials with other agents in the field of prevention of diabetes. And we should anticipate combination treatments in the future. Thank you for your attention. Thank you. Thanks to all our speakers. We are nearly at the end of time and I've been trying to answer all the questions you've put in the chat in the last talk. I want to just bring to this panel, and they've been really interesting. You can feel free to disagree with my answers and all the speakers will be able to stay for a few minutes after. I want to be able to get to the post-test questions. So I was just going to start with the one question which got by far the most upvotes, which is the question with which antibodies are most aggressive. I think we can say that there's no particular antibody that's aggressive because the antibodies themselves are not pathogenic. But for any of the panelists, which antibodies do you worry about most when you see them present? And what about those, anything about those antibodies or the antibody titers that you think about in those spaces? I guess it's a two hour conversation, but I would twist it a little bit and say which antibodies are the most important and we should screen for them. In the younger patients or kids, insulin autoantibody, you cannot leave out from screening. In older people, GAD antibodies are the most important, it's most frequent. And the other question you have about GAD being a single antibody as well. And I think we're doing the consensus monitoring statement. I think GAD in adults is gonna be a very different response than a single GAD in a child potentially. I don't know if you wanna say any more, either of you. So these antibodies against IA2 antigen, they have been proven to be there when the diagnosis is approaching. And the reality is that when we screen in a cross-sectional way, we don't know about the history. So children, for example, they often at young age, they develop insulin autoantibodies, but they tend to lose those antibodies. And then this IA2 antibody is the warning sign, at least for me, and it's proven in Teddy, for example, that when the diagnosis approaches. So please, I appreciate all the questions, they're all excellent. I really liked the one about verapamil and prevention because it's something I've been asking a lot, like when are we gonna do prevention trials with verapamil? I think the question about what needs to be used in combination is really important as well. So thank you guys for your attention and hopefully you enjoyed it, thanks. Thank you.

advances

delaying

onset

type 1 diabetes

immunotherapies

teplizumab

stage two diabetes

adults

pediatric patients

self-tolerance

side effects