exenatide and Drug-Hypersensitivity

Exenatide, a synthetic peptide originally isolated from salivary secretions of Heloderma suspectum, like other subcutaneously injected peptides, can cause antibody formation. Despite that antibody formation has been observed in some patients, results from previous clinical trials have not shown safety and efficacy concerns in exenatide-naïve patients. The objective of this multicenter, open-label study was to investigate the response of anti-exenatide antibody formation and the incidence of immune-related and hypersensitivity reactions after exenatide re-exposure. Fifty-eight patients (57% male; 59+/-10 years; weight 85+/-19kg; HbA1c 8.1+/-0.9%; duration of diabetes 10+/-5 years) were enrolled. At study initiation, 98.3% of patients were taking 1 or more antidiabetes drugs, including oral medication and various types of insulin. Treatment-emergent adverse events (TEAEs) at any time during the study were observed in 40 and 47% of patients with positive and negative treatment-emergent antibodies, respectively. Immune-related AEs were observed in 6 patients (4 were antibody positive). These AEs had not been reported in their previous exposure to exenatide. Re-exposure to exenatide did not result in increased hypersensitivity reactions. Overall, 72% of patients had a baseline to endpoint reduction in HbA1c (range -0.1 to -2.8%), and 87% of antibody negative versus 62% of antibody positive patients had an HbA1c endpoint reduction. The study design and the patients' baseline characteristics, including diabetes treatment at study initiation, are confounding factors limiting clinical conclusions on exenatide's glycemic effect in this patient population. The study results indicate that anti-exenatide antibody formation did not increase the incidence of TEAEs in patients re-exposed to exenatide.

Topics: Aged; Antibodies; Diabetes Mellitus, Type 2; Drug Hypersensitivity; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Treatment Outcome; Venoms

Peptide-based therapies have the potential to induce antibody formation if the molecules differ from a native human peptide. Several reports have disclosed the occurrence of antibody generation in a patient treated with exenatide. The immune response can be problematic from a clinical stand point, particularly if the antibodies neutralize the efficacy of the biotherapeutic agent or cause a general immune reaction. To overcome this limit, PEGylated exendin-4 analogs were designed and examined for metabolic stability and biological activity. To develop an extended release delivery system for exendin-4 for the safe and effective delivery of bioactive exendin-4 without peptide acylation and immunogenicity, PEGylated exendin-4 was encapsulated into poly (lactic-co-glycolic acid) (PLGA) microspheres by w/o/w double emulsion solvent evaporation method. Peptide-loaded microspheres were characterized in terms of morphology, particle diameter, and peptide encapsulation efficiency. Then, the release profile of the peptide from PLGA microspheres and the acylated products from PLGA polymer degradation was determined. The results obtained showed that the stability of exendin-4 was greatly improved by PEGylation. Moreover, eliminated acylation during PLGA polymer degradation in vitro and reduced immunogenicity in vivo were observed. The findings demonstrate that PEGylated exendin-4-loaded microspheres may be a safe and biocompatible system for clinical development.

Topics: Acylation; Animals; Antibodies; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Compounding; Drug Hypersensitivity; Exenatide; Half-Life; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Lactic Acid; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Microspheres; Peptides; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Random Allocation; Rats, Sprague-Dawley; Solubility; Suspensions; Venoms

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists-which can be dosed to pharmacologic levels-act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%-1.7%) compared with DPP-4 inhibitors (0.4%-1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Hypersensitivity; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Pancreatitis; Peptides; Receptors, Glucagon; Venoms