Type 1 Diabetes Intervention Trial Results a Mixed Bag

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]).

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 A_1c 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.

A phase III study of the anti-CD3 drug oteliximab in 240 newly diagnosed type 1 diabetes patients also produced negative findings. The dose – one-sixteenth of that used in previous trials – had been chosen to reduce adverse events seen previously, particularly Epstein-Barr virus activation. The low dose was not effective in preserving C-peptide. This study, dubbed DEFEND, was funded by Tolerx, with support from the Juvenile Diabetes Research Foundation.

"This is clearly an important pathway. Further studies will try to increase that dosage to duplicate the previous efficacy with fewer side effects," said Dr. Peter Gottlieb, professor of medicine and pediatrics at the University of Colorado, Denver.

Another compound under study, DiaPep277, was developed with the goal of preventing beta-cell destruction. Created by the removal of 24 of 500 amino acids from a "heat shock" protein involved in beta-cell destruction via T-cell activation, DiaPep277 had been shown to change destructive T cells into cytokine-secreting protective T-cells in mouse models of type 1 diabetes.

In one phase II study, injections of DiaPep277 in 100 newly diagnosed patients with type 1 diabetes preserved beta-cell insulin secretion for up to 2 years following diagnosis, said Dr. Itamar Raz, professor of medicine and director of the Hadassah Diabetic Center in Jerusalem, Hadassah Hebrew University Hospital.

DiaPep277 is currently in two phase III trials in which beta-cell function, insulin use, and glucose control are being monitored as key outcomes in more than 450 patients per trial. Results for one of the studies are expected by early next year, Dr. Raz said.

Dr. Skyler is an advisory panel and/or board member for a long list of companies that make diabetes-related products. He holds stock in and/or is a shareholder of Amylin Pharmaceuticals, Circulat Biotech, Dexcom, Ideal Life, Inspire Pharmaceuticals, Moerae Matrix, and Tandem Diabetes Care.

Dr. Gitelman and Dr. Sherry stated that they have no disclosures. Dr. Orban serves on the data safety monitoring board for Osiris Therapeutics and is a founding member of Orban Biotechs LLC. Dr. Gottlieb receives research funding from Tolerx, GlaxoSmithKline, MacroGenics, and Diamyd. He has consulted for Eli Lilly, Sanofi-Aventis, and Genentech.

Dr. Raz is a board member of, serves on the advisory panel for, is on the speakers bureau, or is a consultant for AstraZeneca LP, Bristol-Myers Squibb, Novo-Nordisk Pharma Ltd., Roche Pharmaceuticals, and Andromeda.

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]).

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 A_1c 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.

A phase III study of the anti-CD3 drug oteliximab in 240 newly diagnosed type 1 diabetes patients also produced negative findings. The dose – one-sixteenth of that used in previous trials – had been chosen to reduce adverse events seen previously, particularly Epstein-Barr virus activation. The low dose was not effective in preserving C-peptide. This study, dubbed DEFEND, was funded by Tolerx, with support from the Juvenile Diabetes Research Foundation.

"This is clearly an important pathway. Further studies will try to increase that dosage to duplicate the previous efficacy with fewer side effects," said Dr. Peter Gottlieb, professor of medicine and pediatrics at the University of Colorado, Denver.

Another compound under study, DiaPep277, was developed with the goal of preventing beta-cell destruction. Created by the removal of 24 of 500 amino acids from a "heat shock" protein involved in beta-cell destruction via T-cell activation, DiaPep277 had been shown to change destructive T cells into cytokine-secreting protective T-cells in mouse models of type 1 diabetes.

In one phase II study, injections of DiaPep277 in 100 newly diagnosed patients with type 1 diabetes preserved beta-cell insulin secretion for up to 2 years following diagnosis, said Dr. Itamar Raz, professor of medicine and director of the Hadassah Diabetic Center in Jerusalem, Hadassah Hebrew University Hospital.

DiaPep277 is currently in two phase III trials in which beta-cell function, insulin use, and glucose control are being monitored as key outcomes in more than 450 patients per trial. Results for one of the studies are expected by early next year, Dr. Raz said.

Dr. Skyler is an advisory panel and/or board member for a long list of companies that make diabetes-related products. He holds stock in and/or is a shareholder of Amylin Pharmaceuticals, Circulat Biotech, Dexcom, Ideal Life, Inspire Pharmaceuticals, Moerae Matrix, and Tandem Diabetes Care.

Dr. Gitelman and Dr. Sherry stated that they have no disclosures. Dr. Orban serves on the data safety monitoring board for Osiris Therapeutics and is a founding member of Orban Biotechs LLC. Dr. Gottlieb receives research funding from Tolerx, GlaxoSmithKline, MacroGenics, and Diamyd. He has consulted for Eli Lilly, Sanofi-Aventis, and Genentech.

Dr. Raz is a board member of, serves on the advisory panel for, is on the speakers bureau, or is a consultant for AstraZeneca LP, Bristol-Myers Squibb, Novo-Nordisk Pharma Ltd., Roche Pharmaceuticals, and Andromeda.

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]).

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 A_1c 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.

A phase III study of the anti-CD3 drug oteliximab in 240 newly diagnosed type 1 diabetes patients also produced negative findings. The dose – one-sixteenth of that used in previous trials – had been chosen to reduce adverse events seen previously, particularly Epstein-Barr virus activation. The low dose was not effective in preserving C-peptide. This study, dubbed DEFEND, was funded by Tolerx, with support from the Juvenile Diabetes Research Foundation.

"This is clearly an important pathway. Further studies will try to increase that dosage to duplicate the previous efficacy with fewer side effects," said Dr. Peter Gottlieb, professor of medicine and pediatrics at the University of Colorado, Denver.

Another compound under study, DiaPep277, was developed with the goal of preventing beta-cell destruction. Created by the removal of 24 of 500 amino acids from a "heat shock" protein involved in beta-cell destruction via T-cell activation, DiaPep277 had been shown to change destructive T cells into cytokine-secreting protective T-cells in mouse models of type 1 diabetes.

In one phase II study, injections of DiaPep277 in 100 newly diagnosed patients with type 1 diabetes preserved beta-cell insulin secretion for up to 2 years following diagnosis, said Dr. Itamar Raz, professor of medicine and director of the Hadassah Diabetic Center in Jerusalem, Hadassah Hebrew University Hospital.

DiaPep277 is currently in two phase III trials in which beta-cell function, insulin use, and glucose control are being monitored as key outcomes in more than 450 patients per trial. Results for one of the studies are expected by early next year, Dr. Raz said.

Dr. Skyler is an advisory panel and/or board member for a long list of companies that make diabetes-related products. He holds stock in and/or is a shareholder of Amylin Pharmaceuticals, Circulat Biotech, Dexcom, Ideal Life, Inspire Pharmaceuticals, Moerae Matrix, and Tandem Diabetes Care.

Dr. Gitelman and Dr. Sherry stated that they have no disclosures. Dr. Orban serves on the data safety monitoring board for Osiris Therapeutics and is a founding member of Orban Biotechs LLC. Dr. Gottlieb receives research funding from Tolerx, GlaxoSmithKline, MacroGenics, and Diamyd. He has consulted for Eli Lilly, Sanofi-Aventis, and Genentech.

Dr. Raz is a board member of, serves on the advisory panel for, is on the speakers bureau, or is a consultant for AstraZeneca LP, Bristol-Myers Squibb, Novo-Nordisk Pharma Ltd., Roche Pharmaceuticals, and Andromeda.