Innovative Medicines Initiative (IMI) projects INNODIA and INNODIA-HARVEST set up clinical trials of treatments designed to prevent and cure type 1 diabetes. Today, the INNODIA team is announcing the first trial results at the annual meeting of the European Association for the Study of Diabetes (EASD), and in The Lancet. Ahead of the announcement, we sat down with INNODIA coordinator Chantal Mathieu of University Hospital Leuven to find out more about these promising results.
Hello Chantal, thank you for talking to me today. In a nutshell, what is this study about?
Using an innovative trial design from the INNODIA project, we were able to test the impact of different dosages of anti-thymocyte globulin (ATG) on children and young adults with new onset clinical type 1 diabetes and see how well the different dosages preserved beta cell function.
We were able to establish a minimum effective dose of anti-thymocyte globulin, in a relatively short period of time, at lower costs and with fewer participants than a traditional clinical trial would require. The most pronounced benefits of this treatment were seen in the youngest group of children, those aged 5-9.
What makes this treatment better than what’s currently on the market?
We have no approved disease-modifying therapy for people with clinical type 1 diabetes. Nothing is available right now in Europe to arrest the progression of this disease.
What is anti-thymocyte globulin?
Anti-thymocyte globulin is a treatment that is commonly used at high doses to help prevent a person’s body from rejecting a transplanted organ. It’s the immune system that attacks transplanted organs and it’s the immune system that attacks the pancreas beta cells in type 1 diabetes. We know it’s safe – this drug has been in use for about 35 years. In this trial, we are using doses that are 5-10 times lower than those that are used after transplantation, and that’s novel.
Can you explain the role of the beta cells in diabetes?
The main role of beta cells in the pancreas is to produce and secrete insulin, a hormone that we need to regulate and move the glucose in our blood. The body’s main source of energy is glucose, but if a person has diabetes the glucose is trapped in the blood and can’t enter the body’s cells. For people with type 1 diabetes in particular, this is very dangerous. If the body doesn’t have access to glucose, the liver begins to burn fat for energy instead. This process results in acidic chemicals called ketones leaking into the blood, and too many of these ketones building up in the blood can result in death.
When you have type 1 diabetes, your beta cells begin to lose function. What ATG does, is it slows down the rate at which these beta cells die.
This is very important, especially in younger people and children who are diagnosed with diabetes, because the decline of beta cell functioning is much more rapid in children.
Why do children lose beta cell functioning faster than adults?
Because of the attacks of the immune system. If you have an immune system that is extremely aggressive, you will get type 1 diabetes as a child. If you have an immune system that is just a little bit aggressive, you may be an adult before the disease appears. So when you have a child presenting with diabetes, you know that they have an aggressive immune system and for that reason, the beta cells will disappear more rapidly.
Why was it important to determine the lowest effective dose?
First of all, the 0.5 mg dose means just one day of infusion, whereas for the 2.5 mg dose you have two days of infusions. That makes a big difference in burden, in particular for the little children. Our study also illustrated that the chances of having serum sickness, which involves a rash, joint pain and fever, were dramatically reduced if the lower dosage was taken. Serum sickness occurred in 82% of patients who received the higher dose (2.5) and only 32% who received the lower dose (0.5).
Overall, the 0.5mg dose was as efficacious as the 2.5mg dose, but with less side effects and it was also less cumbersome as you only needed one infusion during one day. In our study of course, all was done double-blind, so everybody received two days of infusion (with those in the 0.5mg arm getting a placebo on the second day).
What are the advantages of using this innovative trial design?
With this study, we showed that this clinical trial design that was developed as part of INNODIA worked: it allowed us to get solid information in a short time period. It was an adaptive trial design with very complex statistics, and it allowed us to draw conclusions on a small group while testing several doses simultaneously.
We managed to test four doses and a placebo at once, which is very important. If you were doing this in a classical way, one dose versus placebo, it would take you 10 years before you could get this answer. Now it took us from November 2020 to end of 2024, so even with the COVID pandemic interfering, a big gain of time.
Can this protocol be used for other types of drugs?
Absolutely! Let’s stop doing trial per trial, drug dose A, drug dose B. If we can move the field faster, hopefully in a few years we will have answers and our first alternatives for people with Type 1 diabetes.
What are the next steps?
The drug that we used for this trial was derived from rabbits, and the human body develops antibodies against those cells after the first treatment. What that means is that rabbit ATG treatments can only be used once in a person’s life. But the clinical trial network that is the legacy of the project, also called INNODIA, is currently working with an SME, SAB Bio, which is manufacturing humanised ATG. Our bodies won’t react the same way to humanised ATG, so it could be received more than once.
We are preparing to conduct a trial with humanised ATG where the participants will receive this treatment every six months. The clinical trial sites that are part of the network that was formed as a result of the INNODIA project will run this trial in Europe.
INNODIA and INNODIA HARVEST were supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.