Opinion
Video
Study Design and Key Findings from Teplizumab Clinical Trials in Type 1 Diabetes
Author(s):
Dr Emily Sims reviews the study design of the clinical trials with teplizumab and shares key findings from the completed phase 2 trial.
Emily Sims, MD: The study that the FDA indication was based on was a prevention study. It was people who didn't have what we classically consider as clinical diabetes yet. They met criteria for stage 2 diabetes. These were relatives of people with type 1 diabetes. They were 8 to 45 years of age, and they were stage 2. They already had at least 2 of those islet autoantibodies, and they were already having changes in their blood sugars on an oral glucose tolerance test. You have them drink the glucola, and then you're starting to seeing changes in blood sugars, but not yet meeting those diabetes criteria. These are people who we know are at super, super high risk of progression to clinical diabetes, kind of like right on the edge of getting diabetes. And then they were followed over time after that kind of one-time 14-day course of drug with these oral glucose tolerance tests. They did them 3 months after drug and then 6 months, and then every 6 months over time to catch diabetes early and see if there was any difference in the rates of diabetes development in the people who got placebo or drug.
Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES: Would you be able to share some of the key findings from that trial? How did teplizumab group compare with placebo in terms of that type 1 diabetes progression?
Emily Sims, MD: In the first study that got published in the New England Journal, I think in 2019 they were able to see that treatment with drug was associated with about a 2 year delay in progression of diabetes compared to people who got placebo. And then we did a follow up study a couple of years later that was looking at how people's beta cells made insulin in response to drug versus placebo, and followed people up for longer. And we saw that the effect of drug on the progression of diabetes lasted closer to 3 years. It was 32 and a half months compared to placebo, which was super exciting. And then the other thing that was really, neat is, when you look at the way that people's beta cells make insulin before and after they get the drug. If you follow these people over time before they got treatment, their amount of insulin that they're making is decreasing, decreasing, decreasing. These are kind of right on the edge of getting diabetes, and they're about to go over the cliff. But then- and that continued to be the case for people in the placebo group. But in the people who got drug, you see this cool reversal where they start to increase their insulin production at three months and then at 6 months where they looked significantly different from the placebo group. Not only was diabetes delayed, but it seems like people's beta cells were working better early on after they got this drug pretty quickly.
Natalie Bellini, DNP, FNP-BC: That's incredible.
Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES: It is. Speaking of that, I was actually just curious, because I know there's also the ongoing PROTECT study, which is being done in people with already diagnosed type one diabetes to protect their beta cells. And I believe the protocol for that is a 12-day infusion. I'm just curious if the rationale, if you can share why this one was 14 days, but that one is being done with 12 days?
Emily Sims, MD: I think it's just about convenience for patients. Everyone's super excited about the possibility of these kinds of therapies, but then there's what are the logistics of getting this out to people. And a 14-day infusion means 2 weekends that have to be covered and figuring out weekend coverage for people. And wouldn't it be great if you could get the same effect with a 12 day infusion. And that's the idea, with putting it down to 12 is- probably it has the same benefit, and if it could help patients and be a lot easier for patients to get the drug, then it would be great. And then the PROTECT study, the idea with that study is that in people who have stage 3 diabetes, I think is testing kids. And they're testing 2 doses of the drug kind of right after people get diagnosed and at 6 months with the idea that the prevention study was just one course. Maybe if you could give people a second dose, you could prolong the effect with drug. And the goal would be to preserve people's C-peptide in production. For people who don't study diabetes, C-peptide is the way that we measure someone's endogenous insulin production for people who are taking insulin or getting treated with insulin. And the idea here is that we know that people who have type one diabetes who are still making some of their own C-peptide, long term do much better. It's much easier to manage their diabetes. They usually require less insulin with less low blood sugars. And then in terms of diabetes complications, they also do a lot better over time. That would be the goal with treating right at diagnosis.
Natalie Bellini, DNP, FNP-BC: I have a good question. Of all the studies you've done, what's the longest? We talk about this 24 months or 32 month, what's the longest? Because some people that we've talked to as clinicians have said, it's only 2 years. How long can it be? And again, this is all brand new. And I think people need to understand that this is just the first step, but I would love to know more about how long you have prolonged. And what is the role then of this zinc, the anti-zinc co-transporter antibody versus any other ones? That's a two-part question.
Emily Sims, MD: First question is what's the drug that's had the longest effect on delaying diabetes. This is the only drug that's ever been shown to successfully delay diabetes. Which is the drug, first drug that's had the longest effect. Two things. First of all, this drug we know has an almost 3 year delay on the timing to having diabetes. Which if you think about, particularly for a little kid who's high risk of progressing to diabetes. If you think about 3 years and someone who has a child and not having to take insulin, man, that's like maybe getting through a formative period. Maybe getting through adolescence, where that could make a big difference in your quality of life. And it's going to be an individual decision, but it's something that could impact people and their quality of life. And that said, though, you really hit the nail on the head when you said this is kind of just the first step. There's the possibility of repeated dosing when people start decreasing their own insulin production again. And then most of the people who are in this area, that we're going to have to do some kind of combination therapy long term. The next steps are going to be using other kinds of agents that target other kinds of mechanisms, that maybe could be used in addition to teplizumab. That we could kind of attack this from multiple angles and have longer duration of effects, and ultimately maybe even a cure. But we can find combinations that prolong the need for insulin for a longer period. That was the first part. And then the second part was about different kinds of autoantibodies, and if that makes a difference. We know that depending on which autoantibody you present with, that can be reflective of different kind of phenotypes of type 1 diabetes. And people are recognizing more and more that type 1 diabetes is probably a heterogeneous disease with different people presenting different ways. For example, we know that age, at the time that you present, the age that you present with type 1 diabetes can be associated with different phenotypes. Where people who present as little kids have a much more severe disease course. They progress more rapidly; they lose their own insulin production more quickly. Versus people who present as adults when things kind of seem to move a lot more slowly. And there have been some studies that have shown differences in which autoantibody kind of presents first and which ones you have, and how that may be associated with differences in the way that you present with disease. And the kind of holy grail is we can kind of identify these kinds of differences, including which autoantibodies are positive, and kind of be able to understand what kind of treatments would work the best for different people who have those different phenotypes. We can provide a more precision approach and give the best treatment for each individual person. But for now, the numbers are stillsmall and we're still so early. Those are the steps down the line that we need to cross later.
Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES: That's interesting. I know while 2 or almost 3 years was the median, obviously some people were shorter or longer. I'm curious, what was the longest? How long did it delay in some people for type 1 diabetes?
Emily Sims, MD: It's hard to answer that question because you always want to compare people to placebo. Because even though we were kind of selecting everybody at stage 2, there's probably individual features that make one person not as likely to get diabetes as rapidly than another person. But the last time we followed up the data, there were some people who had gotten drug that it had been over 5 years and they still hadn't progressed to diabetes. And I know that Kevin Herald, who's the person who has been the person who's spearheaded teplizumab in type 1, is planning on looking at people who were kind of long-term responders to teplizumab. And seeing if he can understand some of the kind of individual features that predicts the best response in those individuals.
Natalie Bellini, DNP, FNP-BC: I truly love the idea of then saying, you're a long responder and maybe this is the only drug you need, but you're a short responder and now let's put these 2 together. You might get teplizumab and something else 6 months later. Or you might need teplizumab every 6 months for years, but if you never develop full blown type 1, haven't we done something in the right direction? That's the goal, you mentioned young children. What if I can get that young child through college? Most of them would raise their hand and say, infuse me every 6 months. I've got 12 days or however many days it turns into.
Emily Sims, MD:You know what, maybe a lot of people think it may end up that there's some kind of regimen and then involves an abduction kind of therapy that's something like teplizumab or antithyroglobulin where you have this kind of big hammer that kind of depletes T-cells and then they recover but then you have a maintenance therapy as well that's kind of a less big gun that you could take for longer with kind of less immunomodulation so that it could be a long-term treatment. I totally agree. Even if you must start insulin, maybe if really low doses or just basal or something like that, it still would make a big difference in quality of life and be moving that needle forward.
Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES: The question a lot of people have is, well, what are the adverse effects? How well tolerated is teplizumab? We know it's the infusion. Are the adverse effects just during the infusion or are there some that are kind of lingering later? Can you share some of that?
Emily Sims, MD: Yes. In the PREVENTION study, it was well tolerated. As we mentioned, the logistics of kind of getting a 14-day infusion are kind of annoying. That's one thing. Then you have this drop in your T-cells that recovers kind of over that next month or so and so you must be careful and make sure you're being careful in terms of infectious exposures, but people tolerate the drug really well. The biggest adverse effect in this study was that a lot of people get a rash that usually gets treated with Benadryl® but can be itchy. That's the main issue that people had but otherwise, it was well tolerated and there were no kind of serious safety issues in the study.
Natalie Bellini, DNP, FNP-BC: That's amazing. It really is amazing because usually, we start with tell us the adverse effects and it's 10 minutes of discussion. There really aren't. Patients do. They tolerate it very, very well.
Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES: I'm curious. We talked a little bit, we brushed up a little on the PROTECT study, but what's next for this drug? I imagine we're not stopping here. What is next for teplizumab? Even if you could share some top-line results from PROTECT or if there's other future studies that are planned as well.
Emily Sims, MD: I don't have results yet from PROTECT but one thing is extending the indication potentially to the new onset population, looking at efficacy there. Another thing that is extending the age groups that it's eligible for. The FDA indication was based on the PREVENTION study, which started at age eight, was the lowest age. We know kind of as we mentioned, little kids who are presenting, could benefit from a 3-year delay in their diabetes diagnosis and are the ones who are often progressing the most frequently and are the ones we're kind of hearing about the most. I think prevention is really interested in extending the indication and doing more testing. TrialNet who is the international trial group that put on the initial PREVENTION study is looking at doing a trial on little kids to look at efficacy of the drug in stage 2. The other thing everyone's thinking about is combination regimens. What's going to be a great combination to put with this drug to improve that duration of effect? I'm not aware of a combination trial that has started yet, but there is lots of talk about what those could look like. I'm a big beta cell person, I think it would be cool to try something like verapamil or a drug that targets beta cell health in combination with teplizumab and see if that makes the effect last for longer.
Transcript Edited for Clarity
