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

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

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.

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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.