The Evolution of Anti-CD3 Antibody Clinical Trial
Evolution is sometimes a controversial term, but in medical science, evolution means progress and better understanding.
A couple of years ago, I wrote about the sad news of the anticd3 trials that failed to make their end points. Three separate trials focused on monoclonal antibodies (MABs) and are thought to reduce the destruction of beta cells and encourage the stabilization of c-peptide to help reduce the need for insulin. The focus was to prevent the progress of type 1 diabetes.
Three drugs were developed: Teplizumab, Otelixzumab, and GAD-65 vaccine. The ones that continue to be of interest are the Monoclonal Antibodies therapies, Teplizumab and Otelixzumab.
In a blog from 2011, I mentioned that I had an opportunity to hear Dr. Kevin Herold speak about the importance of anticd3; in particular, Teplizumab, and his desire to push the research forward, despite the disappointing results. His reason was that the research appeared to show a hole in the theory of the development of type 1 diabetes. JDRF stepped up to the plate to help fund Dr. Herold and his anticd3 research.
Since Dr. Herold’s 2011 speech, I have wondered what happened with his push to continue to study anticd3. A couple of weeks ago, an article surfaced that caught my eye: Drug preserves beta cells in new cases of type1 diabetes.
In the original drug trial for anticd3, researchers offered one injection of the drug protocol, which resulted in little beta cell preservation, or c-peptide stabilization. But, this time, the protocol involved two injections, one year apart.
C-peptide is an amino acid protein that connects to insulin, helping to create the synergy to form the insulin molecule. In people with type 1 diabetes, c-peptide is low. What researchers know is that if natural levels of c-peptide levels (called endogenous c-peptide) are low, it's because c-peptide is proportionate to the amount of insulin being made in the pancreas. If c-peptide is low, then type 1 diabetes is present, along with common complications of type 1 diabetes. There are some people who have had long term diabetes that have some level of c-peptide and the correlation is little or no diabetes complications.
In 2010, Macrogenic’s anticd3 trial, Protégé, did not meet its end points, using the drug Teplizumab, a human monoclonal antibody. But under this new trial called AbATE, Teplizumab is proving to be of benefit.
According to Close Concerns, the study randomized people for the study 2:1 and participants either had two, two week courses of Teplizumab (one at diagnosis and one a year later), or they were newly diagnosed patients who were observed and not treated. These participants are called the control group. Of interest were the c-peptide levels. After two years, the group that used the Teplizumab had c-peptide levels that were 75% higher than the control group, and also had reduced the need for insulin. Of the 77 type 1 particpants, here are some of the statistics:
- All were diagnosed within 8 weeks of their first treatment of Teplixzumab.
- Patients ages ranged between 8-30, with the majority being under the age of 18. The mean age of the group was 12.5 years of age.
- Out of the 77 participants, 52 received the second course of treatment, while the remaining 12 did not, due to no detectable c- peptide, or other complications that prevented participation in the second treatment.
What does this mean for newly diagnosed people? If the treatment works, it means a longer honeymoon period. With less destruction of beta cells, the lower the risk for any complications to develop. And, the data regarding c-peptide levels is even more important!
There were two groups: those who responded and those who didn’t respond to the treatment. Every clinical trial suffers this dilemma: is it the drug therapy that is frisky, or the patient's biology? The more researchers can drill down on what differentiates those that respond and those that do not, the better. What biological characteristics are the same for the people who responded versus those who did not?
When it comes to many of these trials that are focused on newly diagnosed type 1 participants, I can’t help but wonder if the test results are a false positive, because of the honeymoon phase of almost everyone living with type 1 diabetes. People can remain in a honeymoon phase for as long as three years, so how do we know if the drug treatment is or isn't working, or if it's the body? Metabolic control also seemed to weigh into the factors contributing to success. Some of the charts from the AbATE trial show my concern:
Karmel Allison wrote a great piece on the results of this trial and I applaud her questions regarding the information. There are so many unanswered questions as to the validity of the treatment, and because of that, I favor more research time on this project.
Chinese philosopher, Lau-Tzu, once said, “The journey of a thousand miles begins with one step.” I am grateful that people like Dr. Herold are still out there hiking the miles!
Note: If you are interested in participating in this clinical trial, recruitment is underway. You can find out more via Trialnet.