Teresa Quattrin, MD, reviews emerging clinical trial data on novel therapies to delay the progression of type 1 diabetes.
Robert Busch, MD: Several of you mentioned that there might be other therapies on the horizon, so even though you’re delaying things 2 to 3 years, there might be something else that comes along. Dr Quattrin, would you like to review some of the other studies with some other novel medications that may be on the horizon?
Teresa Quattrin, MD: It is important while we are focusing on the recent approval that we realize there are also other potential drugs, and they have been used with some success. We talked briefly before about abatacept, there has been a prospective, well-run study with this drug. It prevents T-lymphocyte activation. This drug, for example, at 24 and 36 months, showed that the endogenous insulin measured by the gold standard, which is a C-peptide, was higher in participants. And because this was successful, there is an ongoing study in stage 1 of diabetes. Alefacept is another fusion protein that binds CD4 that also has had promising results. All of these have different variations as to whether they affect the insulin immune surge or hypoglycemia, but ultimately, when I say that they had positive results, I’m alluding to endogenous insulin production.
The other drug that has been published about is a drug that works on B cells because they also contribute directly and indirectly to the autoimmune process. This is rituximab, which is an anti-CD20 antibody, and that also had positive results. At the beginning, Dr Goland mentioned ATG [anti-thymocyte globulin], which has several actions, depleting D cells, and affecting the dendritic cells, which are important in your immune process. That also was a successful study. Now, it’s important to realize that some of these medicines, as pointed out by Dr Simmons, require more premedication and they may have more adverse effects. The other trials I want to bring up, even though this drug is not in development, is the anti-TNF [tumor necrosis factor] agents. After a very successful study, it’s not in development, but that may be an option.
One important thing about the abatacept is that all these studies have what we call responders and nonresponders. Abatacept was also a study where using an algorithm with artificial intelligence, there was this ability to detect who was and wasn’t a responder. Of course, if you take 100 of us adult and pediatric endocrinologists and see if we all agree on who is a responder, how to judge a responder, should it be the insulin-adjusted glycated hemoglobin, should it be the time in range, there is not agreement. But to what Drs Goland and Simmons have nicely outlined, as we move forward, we should be able to collect data so that we make more educated decisions on behalf of patients who are at a high risk of type 1 diabetes.
A lot has been talked about recently regarding the study taking place using a plasmid vector that is designed to transfer DNA into the cells. This is an ongoing study, and it would then alter the process leading to our immunity. There are several ongoing studies that have potential. Unfortunately, studies with subcutaneous insulin or oral insulin, that we hoped would work, ultimately did not meet the end points. I think we base, rightly so, a lot of our tenets on animal models. But when you talk with beta cell physiologists, they eloquently describe the difference, and that’s why we can’t always expect to replicate those trials.
Robert Busch, MD: Will these studies allow people in who have already had teplizumab who haven’t yet developed diabetes to see if you could extend the time when they don’t get diabetes, or does that exclude them from the other studies?
Teresa Quattrin, MD: Typically, patients are naive patients, but I cannot comment as to what might happen with the design of a study. I cannot talk as much about the European system, but the FDA is looking more favorably at adaptive designs. We may be able to do studies where, naturally we see if an individual responds, and if an individual doesn’t respond, then you would stop. One more thing I want to say, the study that led to teplizumab approval was done with 1 infusion, but we don’t have data to say what if we did another infusion. My point is that in rheumatoid arthritis, in Crohn disease, patients have courses of immunomodulators. They are not always kept on chronically, and sometimes the dosing changes based on the response. Frankly, I don’t see why this couldn’t potentially happen for people at high risk for developing stage 2 and stage 3 type 1 diabetes. It should be almost a continuum of the spectrum.
Robert Busch, MD: Dr Simmons, what do you think will be the future of this, given that some of our colleagues will start using it and then it will start snowballing? Do you think it will be the standard of care, that patients who have the 2 antibodies, who have dysglycemia—assuming it’s affordable and can be given more widely at centers—do you think this will be incorporated, just like how pumps or CGMs [continuous glucose monitors] have exploded in the past decade? What do you think will happen down the line with this tool?
Kimberly Simmons, MD, MPH/MSPH: I think it will become the standard of care, hopefully. There is a large transition period to see how that all plays out. But I think if you look at other fields like oncology, for example, where they didn’t have anything, and now they have treatment and these adaptive designs in how they treat patients, I think the future is looking more like that, where there may be repeated drugs, different drugs, and a better ability to predict who will respond and who won’t. Clinical trials as we just discussed will probably have to be designed differently in order to be successfully enrolled. We want to continue doing research because this drug is opening the door, but we want to have other options that are the most beneficial for everybody out there who’s going to develop type 1 diabetes.
Robert Busch, MD: It sounds like in pediatric endocrinology it will be like adult endocrinology, where 30 years ago we had nothing. We had sulfonylurea, but we didn’t have any statins, we didn’t have any good blood pressure drugs. We had NPH [neutral protamine Hagedorn] in regular and double void urines. Compare that to what we have now; it makes practice a lot more fun. I think you’ll be experiencing the same thing in your field as well. You’ve had pumps and sensors, but to have this and the other potential immunomodulators—none of us will ever retire, it’s too much fun to practice. What else is coming out? What about beta cell regeneration and other tools like stem cell transplantation? Dr Goland, if you’d like to take that on.
Robin S. Goland, MD: I’m also never going to retire because I think we might see cell-based therapies for our patients. It’s quite exciting that we’re in a collaborative project where we’re doing skin biopsies, and our colleagues can generate stem cell-derived beta cells that make insulin in the dish. I think that in the next 10 years, we might see the ability to transplant those cells. It’s quite exciting, and like I said earlier, the more options for our patients and their families, the better. We’ve come a long way from NPH…and rightfully so.
Transcript Edited for Clarity