Activity Transcript

Alberto Pugliese, MD: Hello. I'm Dr Alberto Pugliese, the Samuel Rahbar Endowed Chair in Diabetes and Drug Discovery at City of Hope in Duarte, California. Welcome to this program which is entitled Mechanism for Delaying/Preventing Type 1 Diabetes Clinical Onset. Joining me today is Professor Colin Dayan. Colin is a professor of Clinical Diabetes and Metabolism at Cardiff University School of Medicine in the UK. Welcome to our program, Colin.

Colin Dayan, MA, FRCP, PhD: Thank you, Alberto. It's a pleasure to be here.

Dr Pugliese: In terms of pathogenesis of the disease, we consider it a multifactorial disease. There are environmental factors that are considered important, genetic factors as well as autoimmunity all interacting, and eventually leading over time to the chronic loss of pancreatic beta cells, which are the cells that make insulin. And as you can see from these pictures, a normal pancreatic islet is filled with insulin-producing cells or beta cells in red with a good compliment of alpha cells in blue, they secrete glucagon, and in a normal state, you normally do not have any significant presence of lymphocytes attacking the pancreatic islet. But during the course of autoimmunity, typically during the preclinical stages of diabetes, and around the time of onset and beyond, you can see, as in the center picture here, that the islets are under attack. And on top of this particular islet, you can see green cells which represent lymphocytes that are destroying the beta cells. And over time what you're left with are islets that no longer have beta cells, as you can see, there is no red color left, and the lymphocytes have completed their task and have now left.

Now with this background, let's transition to discuss where the unmet needs are for the patients. Colin, can you speak to that please?

Dr Dayan: Yeah. Thanks very much, Alberto. The data that are shown in this slide is showing how far off the goal we are. The red line shows an glycated hemoglobin (HbA1c) of 7.0%, which we know is the level which will reduce the risk of long-term complications to very low levels. And you can see here in these data have taken from over 10,000 individuals in the US that at no time is the average HbA1c meeting that target. And indeed, I want to emphasize there that particularly in younger individuals, in the youth, then they're way above target with mean HbA1c’s of 8.5 to 9.0%. If we could really get on top of that period, that would be a great benefit.

Dr Pugliese: Thank you, Colin. And let me show these particular data here, which are important because they derive from studies that have been done over the last decade or more where individuals at risk have been followed to the diagnosis of T1D being identified during their preclinical phases by autoantibody screening. And patients who have been diagnosed have been followed after diagnosis, so that one could measure the decline of insulin secretion over time. And this is measured by assessing the levels of C-peptide, which, as you know, is a surrogate marker for insulin production as it derives from the proinsulin molecule. And what you can see here, the different color bands represent different age groups. The younger patients are on the bottom in blue, 6 to 11 years of age, and so forth, going up in age. And what you can see is that the arrow marks the time of diagnosis of clinical onset. And especially about 6 months prior to the diagnosis, you appreciate a steeper decline of insulin secretion, and that decline continues at about the same rate for about another 6 months after diagnosis. So that peri-diagnosis period appears to be very aggressive in terms of disease progression. And that's a very important recognition, because it does say that that period of time is ideal to try to preserve insulin secretion more effectively if we're targeting a disease stage where that is occurring at the greater rate.

But also important is that many patients when they're diagnosed still maintain significant residual insulin secretion. From pathology studies, there is also evidence that there is actually a physical mass of residual beta cells in the pancreas that is much greater than had been previously appreciated. These 2 concepts are important because they tell us there is good reason to intervene. And trying to save those beta cells would actually make wonders in terms of improving the unmet need that Colin has just described.

When we look at this figure here, we're really exemplifying the concept that T1D develops over a period of time. And we have been able now to classify this progression in different preclinical stages and clinical stages that are important in terms of addressing therapies for T1D. And these stages are shown in this slide which have been defined by JDRF, the Endocrine Society, and the American Diabetes Association. And what you can see is that the green color here represents, essentially, in the normal state on the far left, the functional beta cell mass that an individual is born with. And over the progression of the disease you can see that this beta cell mass progressively declines. And on top of this slide you can see 3 stages, 1, 2, and 3. And these 3 stages are defined by measuring autoantibodies and assessing metabolic function. And so if an individual has at least 2 different autoantibodies in the circulation, but still has normoglycemia and is presymptomatic as well, that individual is a stage 1, which is already a significant risk of progression to T1D. A stage 2, in addition to having those autoantibodies, individuals will also have dysglycemia. So their glucose metabolism is now abnormal, and it can be measured by metabolic testing, but they're still asymptomatic. And this is a stage where interventions are possible as well, and we will talk about targeting patients at this stage. And stage 3 is the clinical stage where symptoms are now becoming apparent and insulin therapy is required. This classification provide a framework for designing clinical research studies, and trials, and identifying new therapy. And it opens the door, really, for preventing T1D.

And so I'll ask Colin to tell us why it is important that we try to prevent T1D.

Dr Dayan: Thank you, Alberto. Yes. When people ask me, is it worth preventing it? I say, well, yeah, sure it is, because during this period you don't need insulin. If you don't have insulin, there is no risk of hypoglycemia and there's no lifestyle restrictions. You don't even need to monitor your blood sugars because they will be well regulated by endogenous insulin. At the same time, you're getting years of near normoglycemia. Or there may be some dysglycemia, but we're talking about HbA1c’s of 6.5% or lower. This is not contributing to your long-term complication risk. In fact, we know that good control for several years at the beginning of your disease gives you a legacy of reduced long-term complications as we saw in the Diabetes Control and Complications Trial (DCCT). So you're racking up all these advantages. What's interesting is if there is a treatment that requires a short-term intervention, then limited compliance is required. And what I mean by that is you don't have to adjust insulin every day, you don't have to think about your meals, and you don't have to think about your exercise. You've had the treatment. And the last point I've got on this slide refers to the slide I had earlier on, where the most difficult control is in the adolescent period so if we nudge the age of diagnosis on, the age of that stage 3 start on, so it's later. At the moment, it's around the age of 12, but if we nudge it to 13, 14, 15, then the older that you're diagnosed, the less time you spend in adolescence with T1D, and the less problems you have with this period of poor control, which adds to your long-term complications.

In order to identify people that Alberto's mentioned, in stage 1 and stage 2, you can't identify them in the street because they're asymptomatic, and you have to do this by screening for autoantibodies.

We know that a large number of children and adults present in diabetic ketoacidosis (DKA). They've got very little insulin at that point in time and they present very sick. And in some cases, they're very ill and have to be in critical care, and occasionally they die. We can avoid that almost completely by the screening, because the families, and the relatives, and the patients themselves know that it's coming, and they pick up the symptoms very early. We have to remember that 90% of cases come from places where there's no family history, so they've never had any experience of T1D, and the diagnosis is a surprise. They don't understand what's happening. As shown on this slide, there's a dramatic reduction in DKA rates in the screened population down to around 3% or less, and hospitalization becomes a thing in the past. So instead of the majority being hospitalized, now less than 3% need to be hospitalized, because they've been picked up at a stage where you can have a conversation. There's no urgent need for insulin. You can introduce it as an outpatient in the office.

Dr Pugliese: Thank you, Colin. That's very important.

Let's try now to transition to how we can actually implement prevention or delaying the clinical diagnosis of T1D. This has been an evolving field for many, many years, and a number of different therapies that have been tested in clinical trials. For the very first time in late 2022, the FDA has approved, with breakthrough designation, a drug that has the ability to delay, and prevent T1D, and we will discuss the data that supported this approval and the results from this trial. And we'll also discuss the putative mechanism of action for this new therapy.

These are the results from the clinical trial that was conducted in the United States. It was published in the New England Journal of Medicine, and the drug that was used is a monoclonal antibody against CD3, which is, of course, an important target molecule on T-lymphocytes, and is also known as teplizumab in the United States. That was given to relatives of patients with T1D who themselves were at risk for future T1D, because they had tested positive for multiple autoantibodies, and they had reached stage 2 T1D where they have evidence of dysglycemia. The subjects in this study were randomized to either treatment or placebo, and they were followed. And what you can see in the figure is the treated group shown in the blue line and the placebo group in the red line. And as you can see, the curves are quite different. The median time to T1D was 48 months for those treated with the drug, and only 24 months in the placebo group. So much shorter time to T1D. And T1D developed 43% of the participants that were treated, but in 72% of those that were on placebo. The hazard ratio for T1D was 0.41 treated vs placebo. And the analyzed rates for T1D diagnosis were 14.9% per year for the treated group vs 35%, almost 36%, for those in the placebo group. So there was quite a significant therapeutic effect associated with this treatment.

Now the exact mechanism of action of immunotherapies, in general, is not fully known. And in particular for teplizumab, there are some information and theories that are trying to understand how this drug may actually work. We have a 3D animation that tries to illustrate that so let's watch this together.

Voiceover: The IgG antibody is a Y-shaped structure consisting of 4 polypeptides – 2 identical heavy chains and 2 identical light chains. The trunk of the Y, known as the Fc fragment, differs in antibodies of different isotypes. In an effort to reduce potential toxicity when used as a therapy, the Fc region of one such antibody, an anti-CD3 monoclonal antibody known as teplizumab, has been engineered to reduce its binding to the Fc receptor. Specifically amino acids 234 and 235 have been changed to alanine residues in the IgG backbone. With these modifications, this antibody modifies the activity of effector T cells, a key cell type responsible for the immune mediated destruction of beta cells. Antibodies against the T cell component CD3 are not depleting, but rather prevent effector T cells from attacking and destroying beta cells by inducing exhaustion in activated T cells, eventually leading to their anergy or non-activity. Adverse side effects associated with such immunotherapy may include symptoms of cytokine release syndrome, including fever, nausea, headache, gastrointestinal issues, and rapid heart rate, as well as transient lymphocyte losses.

Now that this drug has been approved by the FDA for treating stage 2 diabetes and delaying or preventing progression to stage 3 T1D, I'm sure clinicians would have a lot of questions about how are we going to use it, and what do we expect to see, what the results will be. How safe will it be? This is a single course therapy. It's given intravenously (IV). It's a 14-day course. It does not really represent chronic immunosuppression. It's considered to be more an immunomodulation approach, and it can be given in the hospital setting, it can be given in an infusion center, it can be given in a doctor's office. And I am hearing that, in some cases, it's now being given a patient's homes with professional assistance, especially after the first few doses are proven to be well tolerated.

But it's very important that we talk about safety. And so Colin, can you describe your thoughts, and the data, about this therapy and its safety?

Dr Dayan: Sure, Alberto. I think this is very important. In this slide, it's showing you what happens to T-cell levels after that course. And you can see that they fall rapidly, in the blue line, but then they rapidly return to the same level as placebo. So within 6 weeks, T-cell levels are pretty much completely back to normal. And even when they dip, they don't fall to levels that are like HIV reduction levels, and they're not levels at which there is a significant risk of opportunistic infection. We have to be a little careful over this period of time. But after that, they've returned to normal.

And as you see in the next slide, reports that have happened with teplizumab, it's data that have been followed for 7 years, or a related drug otelixizumab, data that have been followed for 4 years, have not shown beyond this period of therapy that there's any increased risk of infections or malignancies. So the data so far, Alberto, are pretty encouraging.

Dr Pugliese: Thank you, Colin. I think that it's important to share with our audience that there had been a number of trials, in patients with new-onset T1D or stage 3 T1D, where different immunotherapies have been tested trying to identify means to either stabilize or completely abolish the progression of the loss of insulin secretion after diagnosis. And so you can see here, there are 2 trials that tested anti-CD3 therapies, teplizumab, and the other antibody, otelixizumab. And you can see that with anti-CD3 treatment, you have much better preservation of insulin secretion over a period of time. Again, remember the treatment is given, in this case, at the beginning of this trial for a couple of weeks, but then it is stopped, and you can see that the preservation of insulin secretion far outlast the duration of the treatment extending in these lights to 2 years. Now there are other agents that have been used. One is thymoglobulin, for example, again, with data extending to 2 years where you can see here the blue line is thymoglobulin, and the red line is the placebo, and as you can see, there is quite a difference in terms of residual insulin secretion, even 2 years after the treatment. This particular drug was given for 2 days at a low dose at the beginning of the trial. Rituximab is an antibody that targets B-lymphocytes, and it was given again in patients with recent onset T1D, and it was also associated with better preservation of insulin secretion, and so was abatacept, which however was given as a chronic treatment. However, what you can see is that not necessarily insulin secretion is completely stabilized by this treatment. In many cases, it actually continues to decline, but less than in the placebo group. And, you see results from a trial that was conducted using verapamil. You are all familiar with this drug. And it was used, because it is expected to have effects on beta cell function and improving beta cell stress. All of these, besides anti-CD3, have not yet been approved by FDA for treatment, so they remain in the research domain.

I want to hand it over to Colin. Maybe he can give us a little bit of an overview of how to envision the strategies for treating and preventing T1D.

Dr Dayan: Yeah, thanks, Alberto. I think we're entering an era of a completely different paradigm. We're not waiting until the beta cells fail completely and then just step in with insulin, we're getting in there much earlier, because we can detect those earlier stages. So what this is showing here in the green would be a period when you have enough of your own insulin, C-peptide is up on the left hand side, the Y-axis, you have enough of your own insulin that you don't need exogenous insulin. You don't need insulin treatment at all. And that's the best place to stay. As we discussed, you don't have any risk of hypoglycemia, you don't need to monitor, you're in a very good position. The black dotted line is showing you the natural history. So the natural history would be a linear decline showing that you enter then in the yellow zone, which is some people would call the honeymoon, a period when you have some beta cell function, you still need injected insulin, but your glycemic control is a bit easier. And then eventually people end up in the pink, or the orange, or the pink zone when glycemic control is really very tricky, because you've got very little beta cell function left. So now we can change this. For example, in the blue arrow, top left, we can intervene in stage 2 and change that trend. And then we change the direction. So we spend another couple of years, maybe 3 years, in the green zone that we would not have been in before. And then, as Alberto's shown you, there are new treatments coming along, whether that's verapamil or whatever it is, in the orange area, and we can bend things again down the red line, we can actually stay in the good zone for longer and longer. And that means more people can reach the target. Instead of what I showed you at the beginning where less than 30% of people actually reached that glycemic target of 7%, we may be getting to much higher rates, and particularly in the young people, much higher rates of achieving good glycemic control.

Dr Pugliese: Thank you, Colin. That was very clear and helpful. We're coming close to the end of our discussion. Can you give us the takeaways for our learners?

Dr Dayan: Number 1, T1D is an autoimmune disease. It's not primarily a metabolic disease. We need to treat it with immune therapy, and not just wait until we step in with insulin. It's a reminder to all of us that insulin treatment is very challenging. And despite all the technology, the monitoring, the pumps, and the artificial pancreases, still most people don't reach target control levels, and many young people don't want to wear this at all. Treatment with disease-modifying drugs, that means slowing the loss of insulin, as in other autoimmune diseases, can delay or prevent the need for insulin, and even when you do need insulin, it makes metabolic control better. But if you can stay in the zone where you don't need insulin, then everybody can manage their diabetes very well. I would say after 100 years, let's move to what I would call “insulin-free T1D.”

Dr Pugliese: Thank you so much, Colin. This was a great discussion, and it was very inspiring to see this progression of prevention of T1D. Thank you all for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.