Aims: Antibody formation to therapeutic peptides is common. This analysis characterizes the time‐course and cross‐reactivity of anti‐exenatide antibodies and potential effects on efficacy and safety.

Methods: Data from intent‐to‐treat patients in 12 controlled (n = 2225,12–52weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice‐daily (BID) trials and 4 controlled (n = 653,24–30weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52weeks) were analysed.

Results: Mean titres peaked early (6–22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody‐positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody‐positive (45.0% low/11.8% higher titre) at 24–30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment‐emergent anti‐exenatide antibodies from a subset of patients tested did not cross‐react with human GLP‐1 or glucagon. Other than injection‐site reactions, adverse event rates in antibody‐positive and antibody‐negative patients were similar. Efficacy was robust in both antibody‐negative and antibody‐positive patients (mean HbA1c change: −1.0 and −0.9%, respectively, exenatide BID; −1.6% and −1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody‐negative and low‐titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres.

Conclusions: Low‐titre anti‐exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher‐titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection‐site reactions, anti‐exenatide antibodies did not impact the safety of exenatide.