[HTML][HTML] Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

MR Rigby, KM Harris, A Pinckney… - The Journal of …, 2016 - Am Soc Clin Investig
MR Rigby, KM Harris, A Pinckney, LA DiMeglio, MS Rendell, EI Felner, JM Dostou…
The Journal of clinical investigation, 2016Am Soc Clin Investig
BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by
autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept
would result in targeted quantitative and qualitative changes in effector T cells and
prolonged preservation of endogenous insulin secretion by the remaining β cells in patients
with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-
controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk im, separated by …
BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D.
METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses.
RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01).
CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy.
TRIAL REGISTRATION.https://clinicaltrials.gov/ NCT00965458.
FUNDING. NIH and Astellas.
The Journal of Clinical Investigation