SAN DIEGO – Several potential approaches are being attempted to slow the autoimmune progression of type 1 diabetes in newly diagnosed patients, with varying degrees of success.
The studies, funded by government agencies, biotechnology companies, and pharmaceutical manufacturers, are in various phases. "We’re testing things in new-onset type 1 diabetes to see whether or not they modify the course of the disease, and to gain insights as to which ones are safe enough to take into prevention studies. ... The field is in a state of flux at the moment," Dr. Jay S. Skyler said in an interview.
Dr. Skyler chairs the National Institutes of Health–funded Type 1 Diabetes TrialNet study group, which sponsored two of the trials that were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in the Lancet on June 28.
One of those studies, in which new-onset type 1 patients were treated with the antigen glutamic acid decarboxylase (GAD), produced negative results. A total of 145 patients aged 3-45 years who had been diagnosed within the prior 100 days were randomized to either three injections of 20 mcg of GAD formulated with aluminum hydroxide (GAD-alum), two injections of GAD-alum plus one of alum alone, or three injections of alum alone.
At 1 year, the 2-hour area under the curve (AUC) of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0.412 nmol/L in the GAD-alum group, 0.382 nmol/L in the GAD-alum plus alum group, and 0.413 in the alum-only group. Those differences were not significant (Lancet 2011 June 27 [doi:10.1016/S0140-6736[11]60895-7]).
Dr. Jay Skyler
Importantly, however, there were no adverse events. "What we’ve learned is that some of [the agents being tested] don’t work in new onset diabetes, but they are safe. So, they might work earlier in the disease process for prevention. Whether we need a combination of things to really arrest the disease process is another open question," said Dr. Skyler, professor of medicine, pediatrics, and psychology at the University of Miami.
The other TrialNet study involved abatacept (Bristol Myers Squibb’s Orencia), which modulates T-cell costimulation and prevents full T-cell activation. Orencia is currently on the U.S. market for treating adult rheumatoid arthritis and juvenile idiopathic arthritis. In the study, 112 patients were randomized to treatment with either abatacept (77 patients) or placebo (35 patients) intravenous infusions on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years (Lancet 2011 June 28 [doi:10.1016/S0140-6736[11]60886-6]).
Here, there was a significant difference between groups, with the AUC for C-peptide 59% higher with abatacept than placebo at 2 years, and the estimated delay in C-peptide reduction of 9.6 months. However, despite continued administration of abatacept over 24 months, the decrease in beta-cell function with abatacept was parallel to that with placebo after 6 months of treatment, suggesting that T-cell activation lessens with time, said Dr. Tihamer Orban of Joslin Diabetes Center, Boston.
Two additional drugs under study, teplizumab and otelixizumab, are both anti-CD3 monoclonal antibodies that bind to the surface of T-cells and modulate their action. Two studies of teplizumab were presented. In one phase II study called AbATE (anti-cd3 mAb), 52 type 1 patients aged 8-30 years were given two intravenous courses of the drug 1 year apart, while 25 patients received placebo infusions.
There was a significant retention of C-peptide with teplizumab compared with controls. The teplizumab group had a 45% decrease in beta-cell function over 2 years, compared with a 77% reduction in the untreated group, said Dr. Stephen E. Gitelman, professor of clinical pediatrics at the University of California, San Francisco.
The AbATE trial was sponsored by the Immune Tolerance Network, which is funded by the National Institutes of Health. Funding was also provided by the Juvenile Diabetes Research Foundation.
The other teplizumab trial, Protégé, was funded by MacroGenics. It was a 2-year, phase III, double-blind, placebo-controlled, multinational study, with the combined goal of reducing hemoglobin A1c to less than 6.5% for those newly diagnosed with type 1 diabetes and reducing the amount of insulin needed to less than 0.5 units/kg per day.
The primary end point did not differ between the two groups, with 19.8% in the teplizumab group and 20.4% of placebo patients achieving the combined end point at 1 year, said Dr. Nicole Sherry, director of the Diabetes Center at Massachusetts General Hospital for Children in Boston (Lancet 2011 June 28 [doi:10.1016/S0140-6736[11]60931-8]).
However, 5% of the 513 study patients no longer required insulin at 1 year, compared with none of those who received placebo. Moreover, in a post hoc analysis, C-peptide was preserved or increased in 40% of those who received the 14-day regimen of the drug, compared with just 28% of the placebo group. Children were more likely than were adults to retain C-peptide function, as were patients treated within 6 weeks of diagnosis. Adverse events were similar between the two groups, she noted.