Abatacept Delays Beta-Cell Loss in Type 1 Diabetes

PHILADELPHIA – Previous costimulation with abatacept for 24 months was associated with a continued slowing of the decline in beta-cell function 1 year after discontinuation in patients with recent-onset type 1 diabetes.

The findings suggest that abatacept might be useful in prevention studies in individuals at high risk of type 1 diabetes, or as one component in studies that use a combination of different strategies, said Dr. Tihamer Orban, principal investigator in the Type 1 Diabetes TrialNet, through which the study was conducted.

Abatacept, marketed by Bristol-Myers Squibb as Orencia, is a costimulation modulator that was approved to treat rheumatoid arthritis and juvenile idiopathic arthritis. The biologic blocks the process of T-lymphocyte activation that drives the autoimmune destruction of beta-cells leading to type 1 diabetes, according to Dr. Orban.

The current data constitute a follow-up to a randomized, double-masked trial that included 112 patients, aged 6-36 years (mean, 14 years), who had been diagnosed with type 1 diabetes within the previous 100 days. The administration of 27 intravenous infusions of abatacept over 2 years in 77 patients was associated with a 59% higher adjusted C-peptide AUC (area under the curve), compared with the 35 patients who received placebo infusions. The difference (0.378 nmol/L with abatacept vs. 0.238 nmol/L with placebo) was significant. Hemoglobin A_1c was also significantly lower in the abatacept patients, with no difference in insulin use (Lancet 2011;378:412-9).

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, causing the investigators to speculate that T-cell activation lessens with time.

The study remained double-blinded at 36 months. At that point, the mean adjusted 2-hour C-peptide AUC was 0.215 nmol/L for the 64 abatacept patients in whom it was measured, compared with 0.135 nmol/L for the 29 remaining placebo patients. The difference was still significant, said Dr. Orban, who is also an investigator in the section on immunobiology at the Joslin Diabetes Center and an instructor in medicine at Harvard Medical School, both in Boston.

Still, the major effect appeared to be within the first year of the treatment phase, and the two groups remained relatively parallel thereafter. This suggests that the drug may only be actively blocking T-cell activation around the time of diagnosis, he noted.

HbA_1c was significantly lower in the abatacept-treated patients, with no difference in insulin use. In all, abatacept treatment resulted in an average 9.5 months’ delay of loss in beta-cell function, compared with placebo, Dr. Orban said.

"It seems that we may not need a full 2 years of treatment to achieve this effect. It’s very logical to try a shorter course of the drug and see if a similar effect can be achieved," Dr. Orban commented.

This study was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health. Dr. Orban is founder and CEO of Orban Biotech LLC.

PHILADELPHIA – Previous costimulation with abatacept for 24 months was associated with a continued slowing of the decline in beta-cell function 1 year after discontinuation in patients with recent-onset type 1 diabetes.

The findings suggest that abatacept might be useful in prevention studies in individuals at high risk of type 1 diabetes, or as one component in studies that use a combination of different strategies, said Dr. Tihamer Orban, principal investigator in the Type 1 Diabetes TrialNet, through which the study was conducted.

Abatacept, marketed by Bristol-Myers Squibb as Orencia, is a costimulation modulator that was approved to treat rheumatoid arthritis and juvenile idiopathic arthritis. The biologic blocks the process of T-lymphocyte activation that drives the autoimmune destruction of beta-cells leading to type 1 diabetes, according to Dr. Orban.

The current data constitute a follow-up to a randomized, double-masked trial that included 112 patients, aged 6-36 years (mean, 14 years), who had been diagnosed with type 1 diabetes within the previous 100 days. The administration of 27 intravenous infusions of abatacept over 2 years in 77 patients was associated with a 59% higher adjusted C-peptide AUC (area under the curve), compared with the 35 patients who received placebo infusions. The difference (0.378 nmol/L with abatacept vs. 0.238 nmol/L with placebo) was significant. Hemoglobin A_1c was also significantly lower in the abatacept patients, with no difference in insulin use (Lancet 2011;378:412-9).

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, causing the investigators to speculate that T-cell activation lessens with time.

The study remained double-blinded at 36 months. At that point, the mean adjusted 2-hour C-peptide AUC was 0.215 nmol/L for the 64 abatacept patients in whom it was measured, compared with 0.135 nmol/L for the 29 remaining placebo patients. The difference was still significant, said Dr. Orban, who is also an investigator in the section on immunobiology at the Joslin Diabetes Center and an instructor in medicine at Harvard Medical School, both in Boston.

Still, the major effect appeared to be within the first year of the treatment phase, and the two groups remained relatively parallel thereafter. This suggests that the drug may only be actively blocking T-cell activation around the time of diagnosis, he noted.

HbA_1c was significantly lower in the abatacept-treated patients, with no difference in insulin use. In all, abatacept treatment resulted in an average 9.5 months’ delay of loss in beta-cell function, compared with placebo, Dr. Orban said.

"It seems that we may not need a full 2 years of treatment to achieve this effect. It’s very logical to try a shorter course of the drug and see if a similar effect can be achieved," Dr. Orban commented.

This study was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health. Dr. Orban is founder and CEO of Orban Biotech LLC.

PHILADELPHIA – Previous costimulation with abatacept for 24 months was associated with a continued slowing of the decline in beta-cell function 1 year after discontinuation in patients with recent-onset type 1 diabetes.

The findings suggest that abatacept might be useful in prevention studies in individuals at high risk of type 1 diabetes, or as one component in studies that use a combination of different strategies, said Dr. Tihamer Orban, principal investigator in the Type 1 Diabetes TrialNet, through which the study was conducted.

Abatacept, marketed by Bristol-Myers Squibb as Orencia, is a costimulation modulator that was approved to treat rheumatoid arthritis and juvenile idiopathic arthritis. The biologic blocks the process of T-lymphocyte activation that drives the autoimmune destruction of beta-cells leading to type 1 diabetes, according to Dr. Orban.

The current data constitute a follow-up to a randomized, double-masked trial that included 112 patients, aged 6-36 years (mean, 14 years), who had been diagnosed with type 1 diabetes within the previous 100 days. The administration of 27 intravenous infusions of abatacept over 2 years in 77 patients was associated with a 59% higher adjusted C-peptide AUC (area under the curve), compared with the 35 patients who received placebo infusions. The difference (0.378 nmol/L with abatacept vs. 0.238 nmol/L with placebo) was significant. Hemoglobin A_1c was also significantly lower in the abatacept patients, with no difference in insulin use (Lancet 2011;378:412-9).

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, causing the investigators to speculate that T-cell activation lessens with time.

The study remained double-blinded at 36 months. At that point, the mean adjusted 2-hour C-peptide AUC was 0.215 nmol/L for the 64 abatacept patients in whom it was measured, compared with 0.135 nmol/L for the 29 remaining placebo patients. The difference was still significant, said Dr. Orban, who is also an investigator in the section on immunobiology at the Joslin Diabetes Center and an instructor in medicine at Harvard Medical School, both in Boston.

Still, the major effect appeared to be within the first year of the treatment phase, and the two groups remained relatively parallel thereafter. This suggests that the drug may only be actively blocking T-cell activation around the time of diagnosis, he noted.

HbA_1c was significantly lower in the abatacept-treated patients, with no difference in insulin use. In all, abatacept treatment resulted in an average 9.5 months’ delay of loss in beta-cell function, compared with placebo, Dr. Orban said.

"It seems that we may not need a full 2 years of treatment to achieve this effect. It’s very logical to try a shorter course of the drug and see if a similar effect can be achieved," Dr. Orban commented.

This study was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health. Dr. Orban is founder and CEO of Orban Biotech LLC.