Novel glucagon-like peptide-1 analog delivered orally reduces postprandial glucose excursions in porcine and canine models

Abstract

Background: Glucagon-like peptide-1 (GLP-1) and its analogs are associated with a gamut of physiological processes, including induction of insulin release, support of normoglycemia, β-cell function preservation, improved lipid profiles, and increased insulin sensitivity. Thus, GLP-1 harbors significant therapeutic potential for regulating type 2 diabetes mellitus, where its physiological impact is markedly impaired. To date, GLP-1 analogs are only available as injectable dosage forms, and its oral delivery is expected to provide physiological portal/peripheral concentration ratios while fostering patient compliance and adherence.

Methods: Healthy, fasting, enterically cannulated pigs and beagle canines were administered a single dose of the exenatide-based ORMD-0901 formulation 30 min before oral glucose challenges. Blood samples were collected every 15 min for evaluation of ORMD-0901 safety and efficacy in regulating postchallenge glucose excursions.

Results: Enterically delivered ORMD-0901 was well tolerated by all animals. ORMD-0901 formulations RG3 and AG2 led to reduced glucose excursions in pigs when delivered prior to a 5 g/kg glucose challenge, where area under the curve (AUC)0-120 values were up to 43% lower than in control sessions. All canines challenged with a glucose load with no prior exposure to exenatide, demonstrated higher AUC0-150 values than in their exenatide-treated sessions. Subcutaneous exenatide delivery amounted to a 51% reduction in mean glucose AUC0-150, while formulations AG4 and AG3 prompted 43% and 29% reductions, respectively.

Conclusions: When delivered enterically, GLP-1 (ORMD-0901) is absorbed from the canine and porcine gastrointestinal tracts and retains its biological activity. Further development of this drug class in an oral dosage form is expected to enhance diabetes control and patient compliance.

Figure 1

Pharmacodynamic evaluation of ORMD-0901 formulations in glucose-challenged pigs: mean AUC_0–120 of glucose responses of healthy, cannulated pigs to ORMD-0901. Pigs were treated with various formulations of ORMD-0901 containing 50 µg (formulation AG2, n = 4) or 75 µg (formulations RG3 and EG3, n = 6 and n = 3, respectively) exenatide 30 min prior to a glucose challenge of 5 g/kg. Blood was drawn every 15 min from start of experiment, and blood glucose levels were determined using a glucometer. The single asterisk represents p = .041, and the double asterisk represents p = .004.

Figure 2

Glucose responses in glucose-challenged dogs pretreated with ORMD-0901. Mean glucose responses of healthy, cannulated dogs were determined after treatment with glucose alone (squares, n = 4 for each dog) and were graphed as a function of time. Glucose values of dogs treated with subcutaneously delivered exenatide (dashed line, n = 3 for all dogs aside from dog H, where n = 1) or enterically administered ORMD-0901 formulations AG3 (circles, 75 µg exenatide, n = 2 for each dog) or AG4 (diamonds, 100 µg exenatide, n = 3 for each dog) 30 min before glucose challenge were also measured. Blood was drawn every 15 min from start of experiment, and blood glucose levels were determined using a glucometer.

Figure 3

Pharmacodynamic evaluation of ORMD-0901 formulations in glucose-challenged dogs: mean AUC_0–150 of glucose responses of healthy, cannulated dogs to ORMD-0901. Dogs were treated with ORMD-0901 formulation AG3 (n = 8) or AG4 (n = 12), containing 75 or 100 µg exenatide, respectively, 30 min prior to an oral glucose challenge of 80 ml of a 50% dextrose solution + 100 g commercial dog food (7% protein, 6% fat, 1.2% fiber, 80% moisture). For controls, glucose challenge in the absence of exenatide (n = 16) or glucose challenge after subcutaneous injection of 2.5 µg exenatide (n = 10) was performed. Blood was drawn every 15 min from start of experiment, and blood glucose levels were determined using a glucometer. A single asterisk represents p = .068. SC, subcutaneous.