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

Mark R. Rigby, Kristina M. Harris, Ashley Pinckney, Linda A. DiMeglio, Marc S. Rendell, Eric I. Felner, Jean M. Dostou, Stephen E. Gitelman, Kurt J. Griffin, Eva Tsalikian, Peter A. Gottlieb, Carla J. Greenbaum, Nicole A. Sherry, Wayne V. Moore, Roshanak Monzavi, Steven M. Willi, Philip Raskin, Lynette Keyes-Elstein, S. Alice Long, Sai KanaparthiNoha Lim, Deborah Phippard, Carol L. Soppe, Margret L. Fitzgibbon, James McNamara, Gerald T. Nepom, Mario R. Ehlers

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)3285-3296
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number8
DOIs
StatePublished - Aug 3 2015

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Type 1 Diabetes Mellitus
C-Peptide
Hypoglycemic Agents
Insulin
T-Lymphocytes
Placebos
Area Under Curve
Meals
alefacept
Therapeutics
Control Groups
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Rigby, M. R., Harris, K. M., Pinckney, A., DiMeglio, L. A., Rendell, M. S., Felner, E. I., ... Ehlers, M. R. (2015). Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. Journal of Clinical Investigation, 125(8), 3285-3296. https://doi.org/10.1172/JCI81722

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. / Rigby, Mark R.; Harris, Kristina M.; Pinckney, Ashley; DiMeglio, Linda A.; Rendell, Marc S.; Felner, Eric I.; Dostou, Jean M.; Gitelman, Stephen E.; Griffin, Kurt J.; Tsalikian, Eva; Gottlieb, Peter A.; Greenbaum, Carla J.; Sherry, Nicole A.; Moore, Wayne V.; Monzavi, Roshanak; Willi, Steven M.; Raskin, Philip; Keyes-Elstein, Lynette; Long, S. Alice; Kanaparthi, Sai; Lim, Noha; Phippard, Deborah; Soppe, Carol L.; Fitzgibbon, Margret L.; McNamara, James; Nepom, Gerald T.; Ehlers, Mario R.

In: Journal of Clinical Investigation, Vol. 125, No. 8, 03.08.2015, p. 3285-3296.

Research output: Contribution to journalArticle

Rigby, MR, Harris, KM, Pinckney, A, DiMeglio, LA, Rendell, MS, Felner, EI, Dostou, JM, Gitelman, SE, Griffin, KJ, Tsalikian, E, Gottlieb, PA, Greenbaum, CJ, Sherry, NA, Moore, WV, Monzavi, R, Willi, SM, Raskin, P, Keyes-Elstein, L, Long, SA, Kanaparthi, S, Lim, N, Phippard, D, Soppe, CL, Fitzgibbon, ML, McNamara, J, Nepom, GT & Ehlers, MR 2015, 'Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients', Journal of Clinical Investigation, vol. 125, no. 8, pp. 3285-3296. https://doi.org/10.1172/JCI81722
Rigby, Mark R. ; Harris, Kristina M. ; Pinckney, Ashley ; DiMeglio, Linda A. ; Rendell, Marc S. ; Felner, Eric I. ; Dostou, Jean M. ; Gitelman, Stephen E. ; Griffin, Kurt J. ; Tsalikian, Eva ; Gottlieb, Peter A. ; Greenbaum, Carla J. ; Sherry, Nicole A. ; Moore, Wayne V. ; Monzavi, Roshanak ; Willi, Steven M. ; Raskin, Philip ; Keyes-Elstein, Lynette ; Long, S. Alice ; Kanaparthi, Sai ; Lim, Noha ; Phippard, Deborah ; Soppe, Carol L. ; Fitzgibbon, Margret L. ; McNamara, James ; Nepom, Gerald T. ; Ehlers, Mario R. / Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 8. pp. 3285-3296.
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T1 - Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

AU - Rigby, Mark R.

AU - Harris, Kristina M.

AU - Pinckney, Ashley

AU - DiMeglio, Linda A.

AU - Rendell, Marc S.

AU - Felner, Eric I.

AU - Dostou, Jean M.

AU - Gitelman, Stephen E.

AU - Griffin, Kurt J.

AU - Tsalikian, Eva

AU - Gottlieb, Peter A.

AU - Greenbaum, Carla J.

AU - Sherry, Nicole A.

AU - Moore, Wayne V.

AU - Monzavi, Roshanak

AU - Willi, Steven M.

AU - Raskin, Philip

AU - Keyes-Elstein, Lynette

AU - Long, S. Alice

AU - Kanaparthi, Sai

AU - Lim, Noha

AU - Phippard, Deborah

AU - Soppe, Carol L.

AU - Fitzgibbon, Margret L.

AU - McNamara, James

AU - Nepom, Gerald T.

AU - Ehlers, Mario R.

PY - 2015/8/3

Y1 - 2015/8/3

N2 - 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.

AB - 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.

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