Jane Buckner, MD, President at Benaroya Research Institute at Virginia Mason talks about how an immunotherapy treatment delayed the development of diabetes in some high risk patients.
Interview conducted by Ivanhoe Broadcast News in August 2019.
Tell us a little bit about how this trial worked.
BUCKNER: This is a trial using a drug called teplizumab. It’s a drug that was developed based on discoveries made quite a few years ago that suggested in animal models could prevent diabetes. Over the years, this medication had been tested in individuals with new onset diabetes and showed it had some effect. But, of course, those individuals already had diabetes. What this study did was to ask can we prevent or delay Type 1 diabetes? And to do that, you need a couple of things in place. First, you must be able to predict who is going to get diabetes. In many diseases we can’t predict, but in type 1 diabetes we’ve known for many years that if you have a family member with type 1 diabetes, you’re 15 times more likely to get it. We’ve also learned that if you have antibodies that target the pancreas where you produce insulin, that further increases your risk. So, the study design was to look at individuals. There were 76 participants. Fifty-five of them were under 18. We knew those participants were at very high risk to get diabetes. In fact, they all already showed they were not producing as much insulin as they should. They had more than two antibodies. So, we knew they would get diabetes. We just didn’t know when they enrolled in this trial and they were given the drug teplizumab in the hospital. They had to stay in the hospital for 14 days. Then, they were followed over time to see if they developed diabetes. Our goal was to understand if people who received the drug compared to those who received a placebo and underwent the same procedure without the drug, if there was a difference in the rate of developing diabetes.
What did you find?
BUCKNER: This study took quite a long time with recruiting patients. We followed those patients over several years and what we showed is those who received the medication had a lower rate of developing diabetes. If you look at that as your risk, if we know everyone’s going to develop diabetes, what happened at the end of this study was 75 percent of the placebo treated group already had diabetes, but only 46 percent of the individuals with the treatment had diabetes. What that means is there was at least a two-year delay in development of diabetes from what we would have expected in the placebo treated group. What does delay mean? Because we’ve ended this study, we will continue to follow these patients. Those who have not developed diabetes yet may go on to develop diabetes and then we would have been able to say we delayed it. Some of them may never develop diabetes and then our hope is that we prevented them from going ahead and ever getting it. That’s our ultimate goal … to give a therapy that prevents disease. We can’t make that bold statement based on this, but this is certainly the first time looking at people at very high risk of getting diabetes who don’t yet have it proving that we could delay disease with this treatment. We gave the treatment once and followed the individuals over time. So, it wasn’t taking a pill every day. It was one treatment and we were able to delay two years.
Is it one treatment over 14 days?
BUCKNER: Yes. They had multiple infusions.
What’s the benefit of delaying?
BUCKNER: Type 1 diabetes is a disease that you live with not just every day but every hour and every minute. If you ask people with Type 1 diabetes, could I have a day off, they would certainly say yes. The idea of delaying disease for two years in children and adolescents is a really important time in life for their health, for their growth, for their mental health. So, two more years without this disease is really going to have a huge impact on them both emotionally and physically. Anyone who knows someone with diabetes or lives with it themselves would say a delay of two years is a big deal.
Are there bigger consequences the longer you have diabetes?
BUCKNER: Having long term Type 1 diabetes has many medical complications. We know that part of it is how well you control your glucose with insulin. We have better tools to do that, but still know that we don’t do a good enough job, particularly in adolescence where it’s hard to keep track of things and keep track of your diet and activity. The consequences can be high sugar levels, which can cause cardiovascular disease and means premature heart attacks and other things. It can impair kidney function, impair your vision, and problems of low glucose which is particularly dangerous where you can become unconscious. So, managing the highs and the lows have an outcome in terms of your overall health. We’re doing much better today than we did 20, 30, 40 years ago in terms of how long people with Type 1 diabetes live and how well they live. The difference in their long-term health and happiness will be markedly changed if we can prevent the disease.
What do you do with the information now? Do you continue to study? Do you continue to follow patients? Is there a plan to get this to the general public anytime soon?
BUCKNER: There’s several ways to look at this information. First is how can we now do a study to more fully understand how well it works and who it works in. That is being worked on right now. We aren’t at the point of going to the FDA to ask for approval, but this is the first step to say it’s worth doing that next big study. That’s ongoing work that the company who makes this medication is working on. The other major point is that we have shown we can do a clinical trial in this at-risk population and we can show that it can work. So, maybe there is a whole lot of other therapeutic interventions we could do with this drug. What’s exciting is we’ve all proposed over the years that the important time to treat this disease is before you walk in and need insulin. This study shows we’re right about that, and now we can start thinking about the other possible therapies we could use. It opens the door to many more clinical trials.
And those are already in the research phase?
BUCKNER: Absolutely. There is an ongoing clinical trial in trial net where individuals are getting treated with a drug called abatasa to try to prevent disease. There is another clinical trial that trial net started last year in an earlier lower risk population using a drug called hydroxide chloroquine to see if we can prevent progression towards that high-risk group. That one is an enrolling trial. We’ve also had many proposals in for the next clinical trial we’d like to do because we have so many tools in our tool chest of immunologic therapies, that it’s time to apply it to these people at high-risk for Type 1 diabetes.
Explain to me what trial net is.
BUCKNER: Trial net is a consortium of clinical research groups. There is 25 of them that are all groups both nationally and internationally who study Type 1 diabetes. The goal of Type 1 diabetes trial net is to prevent the diabetes. To do that, they’ve enlisted families of individuals with Type 1 diabetes to participate in their studies and they screen families to know what the risk is for people who already have a relative who has diabetes. From that group, they follow people at high-risk for diabetes over the years so they can understand who’s going to get diabetes, how we predict it, and then those individuals are the ones we go out to and ask if they would like to be in a clinical trial? As a group, not only do they perform the clinical trial, but they also use samples from those clinical trials to ask the important scientific questions. For example, what can we learn from the trial? How can we predict when to treat patients and who to treat with different drugs? So, trial net broadly helps us understand how to predict, prevent, and we hope ultimately cure diabetes.
It was said that trial net is looking for five markers. Can you expand on that a bit?
BUCKNER: When we predict risk for diabetes, or having a family member with diabetes, this means you have a genetic risk. We know some of the genes that are important and look for specific genes that we know put you at high-risk. Then, we look for these auto antibodies. these are proteins made by your body and usually an antibody is made to protect you from an infection. But these antibodies target the islet cells that make insulin in the pancreas. Over the years, scientists have identified a series of these antibodies that have different targets, but all lead to this one cell that makes insulin. In that discussion, we talked about the five different auto antibodies you could have. If you have two or more, we already know you’re at very high-risk. I understand they had four of five, so were at very high-risk when they started this study.
Let’s have you correct the numbers, or percentages that you wanted to.
BUCKNER: In the clinical trial, the outcome showed that 72 percent of the individuals treated with placebo got diabetes and 43 percent of those who received the drug developed diabetes.
Is there anything else you would like to add?
BUCKNER: Well, there’s 1 to 2 million Americans who have Type 1 diabetes. If we can learn how to predict and prevent, we save that many more people from having this lifelong disease. Type 1 diabetes is an autoimmune disease and there are over 80 autoimmune diseases. Our goal at BRI is to predict, prevent, cure and reverse diseases of the immune system, including autoimmune diseases. What we’ve learned from Type 1 diabetes gives us a way to think about how can we prevent other diseases like rheumatoid arthritis, multiple sclerosis, systemic lupus or inflammatory bowel disease? What we learned in this study is not going to only help people at risk for diabetes but has the potential to help people with autoimmunity. Autoimmune diseases affect 1 in 15 Americans. So that has a very broad application.
END OF INTERVIEW
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