American Diabetes Association 79th Scientific Sessions:

Type 1 Diabetes Responsive to Immune Therapy, Delaying Disease Onset

With Carla J. Greenbaum, MD, and Kevan Herold, MD

Results of three clinical and mechanistic trials were featured at the “New Therapeutic Approaches and Insights for Type 1 Diabetes” symposium at the American Diabetes Association Scientific Sessions in San Francisco, California, highlighting advances in the management of type 1 diabetes for those with the condition as well as people at risk.1

In opening the session, Carla Greenbaum, MD, director of the Diabetes Clinical Research Program at Benaroya Research Institute in Seattle, and chair of Diabetes TrialNet, said; “We hope to bring wider recognition to the fact that type 1 diabetes (T1D) is an autoimmune disease that is responsive to immune therapy in a similar way as other autoimmune diseases.”

Family members of someone with type 1 diabetes are at 15-fold increased risk of developing the disease..

As a major advance in type 1 diabetes, now we CAN identify those who will develop the disease, Dr Greenbaum told EndocrineWeb. “We now consider that individuals with multiple antibodies and normal glucose tolerance have Stage 1 disease. With multiple antibodies and abnormal glucose tolerance, the patient is considered at Stage 2 disease. In both cases, individuals feel fine and have no symptoms.”2

“Also, we now understand that essentially all close relatives of patients with type 1 diabetes who also harbor multiple antibodies are considered to have an early, asymptomatic form of the disease,” Dr. Greenbaum said. Family members of patients with type 1 diabetes are at 15 times greater risk of developing type 1 diabetes than individuals in the general population.1

“Just as we treat the asymptomatic presence of hypertension to prevent a heart attack or a stroke,” she said, “the findings from the TrialNet studies provide strong evidence that we are approaching a future in which we can identify and treat type 1 diabetes long before symptoms occur.”3-5

Teplizumab Postpones Diagnosis of Type 1 Diabetes by Two Years

The immunotherapy agent, teplizumaba Fc-receptor, nonbinding, anti-CD3 monoclonal antibody that impacts how certain T cells function—was shown to slow the progression to disease in patients identified as being at high risk of developing T1D, based on results of the TrialNet Teplizumab study.3  

Teplizumab functions by interrupting the autoimmune response, which in the TrialNet studies prolonged insulin secretion in patients recently diagnosed with type 1 diabetes delaying disease onset by two years,3 Dr. Greenbaum said. 

Relatives of patients with type 1 diabetes were enrolled in the study after testing positive for at least two of the five antibodies associated with increased disease risk; these individuals are considered at stage 1 disease.2,3

Using the database from TrialNet’s Pathway to Prevention study,3 Dr. Greenbaum and her research team identified relatives of patients with type 1 diabetes who were confirmed as expressing at least two of five antibodies associated with elevated risk of diabetes and an abnormal glucose tolerance test. Of the 76 individuals enrolled, 55 were under than 18 years of age,

Participants in the Teplizumab Prevention Trial received either teplizumab or placebo over 14 days with daily, 30-minute intravenous drug infusions at designated TrialNet clinical centers. The researchers followed the participants until 42 were diagnosed with type 1 diabetes.3 (Two participants were lost to follow-up.)

“Result of the TrialNet Teplizumab study were unequivocal–the group who received a single two-week course of teplizumab had a two-year delay in development of T1D as compared to the placebo group,” Dr. Greenbaum told EndocrineWeb. And the therapy was well tolerated in both children and adults.

Among patients taking teplizumab, 43% were diagnosed with type 1 diabetes as identified by an oral glucose tolerance test as compared to 72% of those receiving placebo, which was statistically significant. Moreover, the teplizumab-treated group saw a reduced annualized rate of diabetes of 14.9% against 35.9% in the placebo group.3

As with other trials involving teplizumab, patients experienced short-term side effects such as a rash and a low white blood cell count, both of which resolved quickly.1

“This was the first time that immune therapy has been shown to delay progression of type 1 diabetes, which is important given that is it one of the most common chronic diseases of childhood and is also diagnosed in adults,”3 said study investigator Kevan Herold, MD, professor of immunobiology and internal medicine at Yale University School of Medicine in New Haven, Connecticut.

“Since three-quarters of the study population were children, we will continue to follow them to determine whether they ever develop type 1 diabetes,” Dr. Herold told EndocrineWeb. Our results offer great hope to family members and in the future, possibly to the general public who may be at risk for developing type 1 diabetes."3

"We are a lot closer to the point of using immunotherapy to delay the onset of diabetes than we were before this trial. I would expect such therapy to be used for this purpose before a decade has passed,” he added.  

Insulin Production Appears Preserved with Immunotherapy for New Onset T1D

Results of a second TrialNet study strongly supports the premise that combination therapy with low-dose antithymocyte globulin (ATG) and teplizumab may provide the greatest relative preservation of area under the curve (AUC) C-peptide of interventions for new onset type 1 diabetes.

Michael J. Haller, MD, the TrialNet ATG/GCSF study chair, indicated that 2-h AUC C-peptide levels at one year remain the primary endpoint for most intervention trials in subjects with new onset T1D;1 he is professor and chief, Pediatric Endocrinology at the University of Florida at Gainesville.

This three-arm, randomized, placebo controlled, double-blind, phase 2b ATG-GCSF New Onset Study, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases,4 was designed to build on findings of an earlier pilot study, the results of which suggested that ATG combined with pegylated granulocyte colony-stimulating factor (PEG-GCSF) preserved insulin production in patients with type 1 diabetes.

Antithymocyte globulin is a polyclonal antibody approved for use in preventing kidney transplant rejection whereas G-CSF has been prescribed to increase white blood cell counts in patients receiving chemotherapy.

Dr. Haller and colleagues set out to determine whether ATG alone or in combination with PEG-GCSF would slow loss of insulin production in patients (n = 89) with T1D between the ages of 12 and 45 years who had received a diagnosis within the prior 100 days when initiated early after diabetes onset and were followed for two years.4

Participants were divided into three treatment groups: (1) ATG, (2) ATG combined with GCSF, and (3) placebo. Two-year findings confirmed the continuation of positive effects after the start of treatment:4

  • Low-dose ATG preserved β-cell function and improved insulin production
  • HbA1c levels were significantly lower, which indicated better long-term blood glucose control, in patients treated with ATG alone and those treated with ATG combined with GCSF versus placebo

The findings suggest that low-dose ATG partially preserved β-cell function and reduced HbA1c for two years following therapy in individuals with new-onset type 1 diabetes,1 said Dr. Haller.

“While the approach remains experimental, the fact that results are being maintained for two years is highly significant,” he said. “Any approach that allows patients with type 1 diabetes to produce more of their own insulin and maintain better blood glucose control for this long demonstrates progress toward our ultimate goal of preventing and reversing this terrible disease.”  

“The team plans to continue to conduct mechanistic studies using the samples collected during the study and TrialNet will consider supporting future studies to determine whether ATG alone, or in combination with other drugs, will prevent or delay type 1 diabetes onset.1

Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of T1D 

Tania Habib, PhD, staff scientist at the Benaroya Research Institute, Seattle, Washington, began the presentation, saying, practitioners will benefit from an greater understanding of genetic factors that predispose patients to type 1 diabetes and a need to recognize factors related to the immune response that are altered in patients with type 1 diabetes.5

To develop effective strategies to intervene and prevent disease, however, these factors must be understood in the context of the trajectory of disease progression in type 1 diabetes,1 said Dr. Habib.

While prior studies of B- and T-cell activity have shown favorable effects in patients with established type 1 diabetes, the need to understand the mechanisms behind these changes whether due to islet autoimmunity, disease progression, or secondary to disease, needs to be clarified.5

To address these questions, Dr. Habib and colleagues used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin-2 and regulatory T cell–mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell and interleukin-21 receptor engagement.5

The findings revealed a range of features that indicated evolving responses along the continuum of type 1 diabetes:5

  • Stage-dependent T- and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives from autoantibody-negative immediate relatives that persisted through clinical diagnosis
  • Late features that arose at or near the diagnosis of type 1 diabetes
  • Dynamic features that were enhanced early and blunted at later disease stages.

Furthermore, the investigators explored how these specific phenotypes were influenced by therapeutic interventions. It appears that distinct immune phenotypes arise at different times in the onset of disease and may be transient.5

One year mean AUC C-peptides were adjusted for baseline C-peptide and age and compared to their internal control to retain individual study effects. To further compare differences in AUC C-peptide across trials, rituximab was used as a reference and the percent increase vs rituximab effect was calculated.

Results with agents approved or investigated for new-onset T1D, such as rituximab, abatacept, low-dose ATG (2.5 mg per kilogram of body weight), ATG/granulocyte-colony stimulating factor (GCSF), high-dose ATG (6.5 mg/kg), alefacept, and teplizumab were compared in patients considered at high risk.

Using this methodology, low-dose ATG (164%) and teplizumab (171%) provided the largest relative improvements in AUC C-peptide. Percent effects over rituximab were: high-dose ATG (-43%), alefacept (33%), abatacept (37%), and ATG/GCSF (45%).5

It is becoming clearer that immune processes that precede disease are more nuanced. For example, early stable changes in interleukin-2 responsiveness that precedes or coincides with transiently altered B-cell responses may inform the selection of subjects for sequential immune therapies that first target B cells with rituximab, followed by specific interventions that target enhanced B-cell and Teff responses to promote more sustained preservation of C-peptide,1 according to Dr. Habib.

Applying TrialNet Findings of Type 1 Diabetes to Clinical Practice

All patients should know that their relatives are at a significantly increased risk of developing type 1 diabetes, and can be screened for antibodies, said Dr. Greenbaum. TrialNet.org. In the US, any family member of patient with T1D can provide consent to participate in the study on-line and can receive a kit to test for antibodies at home.     

“In addition to knowing that we can identify people destined to develop T1D, now we are able to delay disease onset with immune therapy,” she said. “This serves to emphasize that T1D is an immune-mediated disease, which should be treated with immune therapy–moving away from treating disease symptoms (ie, high and low blood glucose) and towards therapy that impacts the underlying disease.” 

More focused longitudinal studies of first-degree relatives before and after type 1 diabetes antibodies arise will further distinguish underlying autoimmune mechanisms (genetic risk vs early autoimmune inflammation) to better inform optimal timing of treatment.

In the next phase of TrialNet, family members of people diagnosed with T1D are already being recruited to the Pathway to Prevention Trial as much to identify signs of disease (ie, risk screening) before it develops as to gain insights that may lead to disease prevention.

The authors reported no financial conflicts regarding this work.

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