Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

Abstract

Aims/hypothesis The aim of the study was to examine the 48 month outcome of treating recent-onset type 1 diabetic patients for 6 days with humanised CD3-antibody, ChAglyCD3. Methods Eighty patients, aged 12-39 years, were recruited for a phase 2 multicentre trial and randomised to placebo (n=40) or ChAglyCD3 (n=40) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (U kg −1 day −1 ) over 48 months was chosen as primary endpoint and compared in 31 placeboand 33 ChAglyCD3-treated patients. Adverse events were followed in 35 and 38 patients, respectively. Results Treatment with ChAglyCD3 delayed the rise in insulin requirements of patients with recent-onset diabetes and reduced its amplitude over 48 months (+0.09 vs +0.32 U kg −1 day −1 in the placebo group). Using multivariate analysis this effect was correlated with higher baseline residual beta cell function and a younger age. It was associated with better outcome variables in subgroups selected according to these variables. In the ChAglyCD3 subgroup with higher initial beta cell function, 0/11 patients became C-peptide-negative over 48 months vs 4/9 in the corresponding placebo subgroup. In the subgroup aged <27 years old, antibody treatment preserved initial beta cell function for 36 months (vs >80% decline within 24 months in the placebo subgroup <27 years old), resulted in lower HbA 1c concentrations and tended to reduce glycaemic variability (p=0.08). No longterm adverse events were observed. Conclusions/interpretation A 6 day ChAglyCD3 treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48 months, depending on their age and initial residual beta cell function. In younger patients this effect is associated with reduced deterioration of metabolic variables. These observations help to define inclusion criteria for prevention trials.

Population dynamics of islet-infiltrating cells in autoimmune diabetes

“…Treatment with anti-CD3 is a promising avenue of therapy for T1D. When administered early after disease onset, it has been shown repeatedly to reverse diabetes in NOD mice and preserve residual β-cell function in T1D patients for 12-24 mo (35)(36)(37)(38). Although most diabetic NOD mice treated with anti-CD3 revert to normoglycemia, the treatment does not permanently abolish the autoimmune lesion in the pancreas; rather, a stable state of insulitis is established, with a demarcation between the inflammatory infiltrate and β-cell mass (39, 40) (Fig.…”

Immune therapy in type 1 diabetes mellitus

“…As the end-point of this lower-dose study was not reached both DEFEND and DEFEND-2 was terminated. The four year follow-up of the patients in the Phase II clinical trial indicated a delayed the rise in insulin requirements of patients (43). Furthermore, in a subgroup of the Phase II trial patients it was shown that recall immunity was preserved adding to the aspect of safety (ref).…”

“…The Phase II trial with otelixizumab, a humanized non-mitogenic CD3 (ChAgly CD3) monoclonal antibody in newly diagnosed T1D patients suppressed the rise in insulin requirements over 48 months but the effect was related to age and residual c-peptide at diagnosis 43 . The subsequent industry-sponsored Phase III trial (Durable-Response Therapy Evaluation For Early or New-Onset Type 1 Diabetes -DEFEND, NCT00678886) used a cumulated dose of 3 mg as compared to 48 mg for the phase II study.…”

Antigen-based vs. systemic immunomodulation in type 1 diabetes

“…7 At 48 mo the insulin requirements were still better than the placebo group. 42 In addition they stated that a younger age and higher basal β-cell function significantly correlated with improved clinical outcome. 42 However, in the majority of patients receiving Otelixizumab a short-term transient reactivation of the Epstein-Barr virus (EBV) was observed.…”

“…42 In addition they stated that a younger age and higher basal β-cell function significantly correlated with improved clinical outcome. 42 However, in the majority of patients receiving Otelixizumab a short-term transient reactivation of the Epstein-Barr virus (EBV) was observed. 7,42,43 This self-limited immune response was probably mediated through an activation of EBV-specific T-cells in combination with a short-term general immunosuppression.…”