Struggles with clinical translation of immune intervention trials.

Abstract

Immune intervention trials in type 1 diabetes have shown very mixed, and often surprising, results. Despite suggestions of benefit from GAD-Alum vaccine in a phase 2 study (1), further studies, including two large phase 3 trials, showed no effect (2–4). Phase 3 trials with Anti-CD3 monoclonal antibodies failed to achieve their primary outcome (5–7), despite very promising results from multiple phase 2 trials (8–13). The conflicting Anti-CD3 data may be explained by unfortunate changes in design (5) or dose (6,7) in phase 3 (14). Many immunologic strategies have been tested in phase 2 trials, some with signs of benefit, such as rituximab (15) and abatacept (16); others without benefit, such as mycophenolate mofetil with or without daclizumab (17) or anti-interleukin 1 blockade with either canakinumab or anakinra (18); and others with ambiguous effects, such as thymoglobulin (19) or alefacept (20). In this issue, there are two articles describing results from the phase 3 Efficacy Study of DiaPep277 in Newly Diagnosed Type 1 Diabetes Patients (DIA-AID 1) trial evaluating the safety and efficacy of a 24 amino acid peptide derived from heat shock protein 60, called DiaPep277 (21,22). According to Raz et al. (21) and Pozzilli et al. (22), it appears as if the study demonstrated a beneficial effect, and if so, that would be a very exciting finding. Yet, as outlined below, there are several aspects of the study that make that conclusion less certain. This commentary examines the studies and explores some clinically relevant issues readers may want to consider when interpreting the data from the trial. The principal measure of efficacy in immune intervention trials in type 1 diabetes is preservation of C-peptide as an index of β-cell …