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After several decades of trial and error, researchers for the first time demonstrated that immune therapy could slow the onset of type 1 diabetes in individuals at risk for this chronic condition. A 2-week regimen of teplizumab, an experimental anti-CD3 monoclonal antibody that interferes with the body’s autoimmune destruction of insulin-producing cells, slowed development of the disease by nearly 2 years in high risk patients. Trial investigators presented their results during the American Diabetes Association’s 79th Scientific Sessions in San Francisco and in a New England Journal of Medicine paper.
“This is the first time we have showed that immune therapy can delay progression to type 1 diabetes,” said lead study author Kevan Herold, MD, professor of immunobiology and internal medicine at Yale University, in a statement. “Our results offer great hope to family members and possibly in the future to the general public who may be at risk for developing type 1 diabetes.”
This watershed moment was 30 years in the making. Teplizumab’s developer, Jeffrey Bluestone, PhD, and his colleagues began testing this therapy in the 1990s with mixed results until 2013, when a clinical trial demonstrated that it delayed disease progression in 52 patients who were in the earliest stages of type 1 diabetes and who still had moderate insulin production. Teplizumab essentially blocks the autoimmune response that causes type 1 diabetes, Herold told CLN Stat. “Although there are still questions about the precise mechanism of action of anti-CD3 monoclonal antibodies, our working model is that it induces exhaustion or partial exhaustion of CD8+ T cells largely believed to be important effectors in type 1 diabetes,” Herold explained.
This latest trial, the Teplizumab Prevention Trial, enrolled 76 participants (55 children and 21 adults) with a family history of type 1 diabetes who presented either with abnormal glucose tolerance and at least two types of diabetes-related autoantibodies.
Investigators randomly assigned participants to a treatment group, which received a single 14-day course of teplizumab, or to a placebo group, tracking any progression of clinical type 1 diabetes through regular glucose tolerance tests. Just 43% of the participants in the intervention group developed clinical diabetes, compared with 72% in the control group. The median time for developing diabetes among participants who received teplizumab was also twice as long—48 months, compared with 24 months in the control group. In another promising finding, a higher percentage of the intervention participants remained diabetes-free by the time the trial concluded.
“A median delay of two years compared to a lifetime of diabetes might not sound like a lot, but treating a 10-year-old instead of an 8-year-old or an 18-year-old instead of a 16-year-old is a very big difference, from a clinical perspective,” said Stephen Gitelman, MD, one of the study’s co-authors, in a statement. Some patients experienced short-term side effects common to teplizumab, such as rash and a low white blood cell count.
While promising, the study had limitations. Most notably, it focused on the non-diabetic relatives of patients with type 1 diabetes, identified by the presence of autoantibodies in serum and the results of an oral glucose tolerance test. Most people who present with new onset type 1 diabetes are not going to be the relatives of patients, Herold stressed. “Now that we have a treatment that can at least delay (and potentially prevent) type 1 diabetes, we are wondering whether we should be thinking of a much broader screening strategy” that involves even the general population.
Whether teplizumab treatment actually prevents diabetes in some patients is something that future research needs to address, Herold said. Patients in the study who did not develop diabetes in the teplizumab group “might have developed diabetes the day after the study ended or may never develop diabetes,” he added.
Clifford J. Rosen, MD, and Julie R. Ingelfinger, MD, touched on this concern in a related editorial. “Although the trial showed a marked delay in the onset of overt diabetes, the results should not be taken to imply that immune modulation constitutes a potential curative approach,” they wrote. Considering that Herold and his colleagues’ trial was small in scope, involving just 76 participants and a brief 2-week course of treatment, “the duration and frequency of treatments, the long-term side effects of those therapies, the identification of subgroups of persons who do not have a response to the treatment, and the clinical course of persons who initially do have a response still need to be determined.” That said, these findings represent a substantial leap forward in controlling early onset diabetes, Rosen and Ingelfinger acknowledged.