Clinical relevance of anti‐exenatide antibodies: safety, efficacy and cross‐reactivity with long‐term treatment

Abstract

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.

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

“…Furthermore, sub-chronic administration of [D-Leu-4]-OB3 could potentially lead to the generation of leptin antibodies, although this seems unlikely given the minor structural differences between [D-Leu-4]-OB3 and the native leptin fragment. Moreover, previous clinical studies with leptin have noted non-neutralising effects of antibodies generated against leptin [36,37], in parallel with other observations using similar regulatory peptides [38]. In addition, the prominent beneficial effects of (pGlu-Gln)-CCK-8 on glucose tolerance, insulin sensitivity and triacylglycerol content of adipose and liver tissue were not enhanced by concurrent administration of [D-Leu-4]-OB3.…”

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

“…One subgroup is the exendin-4-based drugs with exenatide and lixisenatide, which are structurally distinct from human GLP-1. Owing to the low amino acid homology to native human GLP-1, these medications are associated with an increased number of immune reactions that are, however, all of a relatively mild form, that is, mostly antibody development, injection site nodules, and loss of efficacy (8,9). The other subgroup is based on human GLP-1 and contains liraglutide, taspoglutide, and larger covalently conjugated molecules such as albiglutide and dulaglutide.…”

Lixisenatide: a once-daily glucagon-like peptide-1 receptor agonist

“…17 This proportion of antibody-positive patients is roughly similar to that shown in studies with exenatide BD and QW, suggesting that antibody formation with lixisenatide is unlikely to impact on efficacy or safety outcomes. 26 In addition to its efficacy, lixisenatide has a number of properties which improve its ease of use. Lixisenatide has a simple one-step dose increase and a single maintenance dose of 20 µg OD for all patients.…”

“…The phase III program comprises two studies, LixiLan-O and LixiLan-L, and is planned to enroll more than 1,800 patients with inadequate glycemic control on oral anti-diabetic drugs or not at target on basal insulin. 26 The OD dosing delivered in a single pen may offer an attractive treatment escalation pathway for patients with inadequate glycemic control. Lixisenatide offers an important add-on option to patients as the diabetes treatment paradigm moves to individualizing patient care.…”

“…16 Addition of lixisenatide to insulin significantly improved 2-h PPG (mean reduction of -3.2 mmol/L vs. placebo, p\0.0001), and resulted in a mean difference in body weight of -0.9 kg compared with placebo (p = 0.0012). Insulin glargine dose increased more in the placebo group ( 25,26 Although the FDA has no requirement for the investigational drug to show superiority to placebo, ELIXA is designed to demonstrate that lixisenatide reduces cardiovascular morbidity and mortality in patients with type 2 diabetes who have recently experienced an acute coronary syndrome event.…”