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Inducing Remission in New Onset T1DM with Alefacept (Amevive®) (T1DAL)

Principal Investigator

Mark Rigby, MD, PhD | Indiana University/Riley Hospital for Children | Indianapolis, IN

Locations

University of Arizona | Tucson, AZ
University of California, San Francisco | San Francisco, CA
Barbara Davis Center for Diabetes at University of Colorado | Aurora, CO
University of Miami Hospital and Clinics | Miami, FL
Emory University/Children's Healthcare of Atlanta | Atlanta, GA
University of Iowa Hospital and Clinics | Iowa City, IA
University of Maryland Medical Center | Baltimore, MD
Massachusetts General Hospital/Partners HealthCare | Boston, MA
Children's Mercy Hospitals and Clinics | Kansas City, MO
Creighton University | Omaha, NE
University of Rochester Medical Center | Rochester, NY
University of North Carolina Diabetes Care Center | Durham, NC
The Children's Hospital of Philadephia | Philadelphia, PA
UT Southwestern Medical School | Dallas, TX
Benaroya Research Institute at Virginia Mason | Seattle, WA
Children’s Hospital of Los Angeles | Los Angeles, CA
Indiana University Riley Hospital for Children | Indianapolis, IN
University of Minnesota Pediatric Endocrinology | Minneapolis, MN
Children’s Hospital at Vanderbilt University | Nashville, TN

Study Code

ITN045AI

Study Status

Completed

Abstract

Basis/Rationale

Despite progress towards understanding the genetic, environmental and immunologic basis for T1DM, the prevention and cure of this condition remains elusive. The autoimmune pathogenesis of T1DM is well established, and several experimental strategies in animal models have focused on preventing disease by an immunomodulatory intervention, specifically through targeting diabetogenic T cells.

If the autoimmune attack is able to be mitigated soon after diagnosis, when it is thought that up to 10-20% of baseline beta cells are still present, then the disease might be able to be stabilized or even reversed.  Proof of concept clinical studies have shown that potent “traditional” immunosuppressive drugs (like cyclosporine or azathioprine) can in some instances reverse diabetes. The long term use of such medicines with significant side effects, particularly in children and adolescents who most often contract the disease, is not feasible.

At this point, clinical trials in T1DM using therapies directed at lymphocytes, and specifically T cells, have the greatest promise for interrupting diabetes autoimmunity and thus inducing remission and re-establishing tolerance in T1DM. One example is by interrupting the interaction between CD2 and the lymphocyte function-associated antigen-3 (LFA-3). CD2 is expressed on T cells and LFA-3 on antigen-presenting cells; following T cell receptor-MHC interaction, the CD2/LFA-3 interaction provides accessory stimulation for T cells. In addition, CD2 is expressed most abundantly on effector-memory T cells and, by bridging these cells with natural killer (NK) cells, induces apoptosis and a reduction in circulating effector-memory T cells.

Alefacept (Amevive®, Astellas Pharma US, Inc.) is an immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding portion of human LFA-3 linked to the Fc portion of human IgG1. Alefacept binds competitively to the CD2 receptor on the surface of T cells with the LFA-3 portion of the drug and thereby efficiently interferes with LFA-3/CD2 interactions and T-cell activation. In addition the Fc portion of alefacept engages the immunoglobulin receptor FcγRIII on the surface of NK cells, resulting in apoptosis of T-cell subsets that express high levels of CD2. Since CD2 expression is higher on effector-memory than naïve or central-memory T cells, alefacept appears to be able to preferentially deplete this highly pathogenic T cell subpopulation that is believed to be involved in active beta cell destruction. 

Alefacept has shown significant efficacy in the T cell-mediated autoimmune disorder of plaque psoriasis. Additionally, animal studies strongly suggest that the CD2 pathway is an integral component in diabetes autoimmunity. In addition to its proven clinical efficacy in psoriasis, a T cell-mediated disease, alefacept treatment has been well-tolerated without causing significantly increased risk for serious infection, malignancy or non-immune side effects, making it an attractive drug for testing in T1DM.

Protocol Summary

Primary Objective:

The primary objective is to determine whether alefacept will slow the progression of the autoimmune destruction of beta cells and lead to the preservation of C-peptide secretion in T1DM, and the primary endpoint is a mixed-meal tolerance test (MMTT) stimulated 2-hour C-peptide AUC at week 52.

Study Design:

This trial will be conducted as a multi-center, prospective, double-blind, placebo-controlled, 66-patient, 2:1 randomized, phase II clinical trial for individuals with recent-onset T1DM aged 12−35 years.  Participants will receive weekly IM injections of alefacept (15 mg) or placebo for 12 weeks, followed by a 12-week pause before resuming another 12 weeks of dosing, for a total course of 24 weeks of alefacept or placebo.

[Clinicaltrials.gov] [Study Website]

Principal Investigator

Mark Rigby, MD, PhD | Indiana University/Riley Hospital for Children | Indianapolis, IN

Locations

University of Arizona | Tucson, AZ
University of California, San Francisco | San Francisco, CA
Barbara Davis Center for Diabetes at University of Colorado | Aurora, CO
University of Miami Hospital and Clinics | Miami, FL
Emory University/Children's Healthcare of Atlanta | Atlanta, GA
University of Iowa Hospital and Clinics | Iowa City, IA
University of Maryland Medical Center | Baltimore, MD
Massachusetts General Hospital/Partners HealthCare | Boston, MA
Children's Mercy Hospitals and Clinics | Kansas City, MO
Creighton University | Omaha, NE
University of Rochester Medical Center | Rochester, NY
University of North Carolina Diabetes Care Center | Durham, NC
The Children's Hospital of Philadephia | Philadelphia, PA
UT Southwestern Medical School | Dallas, TX
Benaroya Research Institute at Virginia Mason | Seattle, WA
Children’s Hospital of Los Angeles | Los Angeles, CA
Indiana University Riley Hospital for Children | Indianapolis, IN
University of Minnesota Pediatric Endocrinology | Minneapolis, MN
Children’s Hospital at Vanderbilt University | Nashville, TN

Articles

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Speake C, Bahnson HT, Wesley JD, Perdue N, Friedrich D, Pham MN, Lanxon-Cookson E, Kwok WW, Sehested Hanson B, von Herrath M, Greenbaum CJ. (2019) Systematic Assessment of Immune Marker Variation in Type 1 Diabetes: A Prospective Longitudinal Study. . Front Immunol, 10, 2023. DOI: 10.3389/fimmu.2019.02023
Pesenacker AM, Chen V, Gillies J, Speake C, Marwaha AK, Sun A, Chow S, Tan R, Elliot T, Dutz JP, Tebbutt SJ, Levings MK. (2019) Treg gene signatures predict and measure type 1 diabetes trajectory. JCI Insight, 4 (6), e123879. DOI: 10.1172/jci.insight.123879 PMID: 30730852 PMCID: PMC6483004 [PubMed] [Reprint]
Habib T, Long SA, Samuels PL, Brahmandam A, Tatum M, Funk A, Hocking AM, Cerosaletti K, Mason MT, Whalen E, Rawlings DJ, Greenbaum CJ, Buckner JH, the Type 1 Diabetes TrialNet Study Group. (2019) Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of T1D Progression. Diabetes, epub ahead of print. DOI: 10.2337/db18-1081 PMID: 30894366 [PubMed]
Dufort MJ, Greenbaum CJ, Speake C, Linsley PS. (2019) Cell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes. JCI Insight, 4 (4), e125556. DOI: 10.1172/jci.insight.125556 PMID: 30830868 PMCID: PMC6478408 [PubMed] [Reprint]
Pinckney A, Rigby MR, Keyes-Elstein L, Soppe CL, Nepom GT, Ehlers MR. (2016) Correlation Among Hypoglycemia, Glycemic Variability, and C-Peptide Preservation After Alefacept Therapy in Patients with Type 1 Diabetes Mellitus: Analysis of Data from the Immune Tolerance Network T1DAL Trial. Clin Ther, 38 (6), 1327-39. DOI: 10.1016/j.clinthera.2016.04.032 PMID: 27209482 PMCID: PMC4916002 [PubMed] [Reprint]
Boyle KD, Keyes-Elstein L, Ehlers MR, McNamara J, Rigby MR, Gitelman SE, Herold KC, Weiner LJ, Much KL. (2016) Two- and Four-Hour Tests Differ in Capture of C-Peptide Responses to a Mixed Meal in Type 1 Diabetes. Diabetes Care, 39 (6), e76-8. DOI: 10.2337/dc15-2077 PMID: 27208317 PMCID: PMC4878222 [PubMed] [Reprint]
Speake C, Odegard JM. (2015) Evaluation of Candidate Biomarkers of Type 1 Diabetes via the Core for Assay Validation. Biomark Insights, 10 (Suppl 4), 19-24. DOI: 10.4137/BMI.S29697 PMID: 26462120 PMCID: PMC4589091 [PubMed] [Reprint]
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 Kanaparthi, Noha Lim, Deborah Phippard, Carol L. Soppe, Margret L. Fitzgibbon, James McNamara, Gerald T. Nepom, Mario R. Ehlers, Immune Tolerance Network T1DAL Study Group. (2015) Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest, 125 (8), 3285-96. DOI: 10.1172/JCI81722 PMID: 26193635 PMCID: PMC4623571 [PubMed] [Reprint]
Rigby MR, DiMeglio LA, Rendell MS, Felner E, Dostou JM, Gitelman SE, Patel CM, Griffin KJ, Tsalikian E, Gottlieb PA, Greenbaum CJ, Sherry NA, Moore WV, Monzavi R, Willi SM, Raskin P, Moran A, Russell WE, Pinckney A, Keyes-Elstein L, Howell M, Aggarwal S, Lim N, Phippard D, Nepom GT, McNamara J, Ehlers MR, Immune Tolerance Network T1DAL Study Team. (2013) Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol, 1 (4), 284-94. DOI: 10.1016/S2213-8587(13)70111-6 PMID: 24622414 PMCID: PMC3957186 [PubMed] [Reprint]
Linsley PS, Greenbaum CJ, GT Nepom. (2021) Uncovering Pathways to Personalized Therapies in Type 1 Diabetes. Diabetes, 7 (4), 831-841. DOI: 10.2337/db20-1185 PMID: 33741606 PMCID: PMC7980192 [PubMed] [Reprint]
Buckner JH, Nepom GT. (2016) Obstacles and opportunities for targeting the effector T cell response in type 1 diabetes. J Autoimmun, Jul (71), 44-50. DOI: 10.1016/j.jaut.2016.02.009 PMID: 26948997 PMCID: PMC4903876 [PubMed] [Reprint]
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The Immune Tolerance Network and is sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

National Institute of Allergy and Infectious Diseases

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