Novel Glucagon-like Peptide-1 Analog Delivered Orally Reduces Postprandial Glucose Excursions in Porcine and Canine Models

Controlled release of biologics for the treatment of type 2 diabetes

“…Future strategies to create orally available incretin formulations may involve active transport of the peptide across the intestinal lumen by conjugation to transportable substrates such as PEG-biotin, which is taken up by sodium-dependent multivitamin transporters [149], and vitamin B 12 , which is scavenged by the body from the diet by various chaperone proteins[150]. Oramed, a pharmaceutical company headed towards phase IIb trials for its oral insulin capsule, is also developing an orally ingestible exenatide capsule (ORMD-0901)[151]. It is evident from these incretin delivery developments that oral peptide delivery could be an area of immense growth in both academia and industry.…”

Glucagon‐Like Peptide‐1 (GLP‐1)‐Based Therapeutics: Current Status and Future Opportunities beyond Type 2 Diabetes

“…This however has not stopped research into the development of orally administered GLP‐1 formulations. Examples of such approaches include oral semaglutide (Figure ), Oramed Pharmaceuticals ORMD‐0901 (exendin‐4 formulated to protect against enzymatic and acid catalyzed degradation, and to improve oral absorption) and biotinylated GLP‐1(7–36)‐NH 2 (at Lys26 and Lys34) . The final example takes advantage of the sodium‐dependent multivitamin transporter, which can facilitate the uptake of biotin‐conjugated peptides from the intestine .…”

“…Apart from its glucose‐dependent stimulation of insulin secretion (insulinotropic effect) and suppression of glucagon activity during hyperglycemia, GLP‐1 also enhances all pathways of insulin biosynthesis and gene transcription in humans and other animals, as well as enhancing satiety (the ‘state of feeling full′) and delaying gastric emptying, which in turn decreases food intake resulting in subsequent weight loss (Figure ) . Further, animal and in vitro studies have revealed that GLP‐1 analogs can also increase β‐cell mass, as well as inhibiting β‐cell apoptosis …”

“…This in turn leads to activation of adenylyl cyclase and subsequent insulin secretion. The circulation half‐life of these active GLP‐1 peptides are extremely short (≈2 min) due rapid enzymatic degradation by endopeptidases, especially dipeptidyl peptidase‐4 (DPP‐4), which cleaves between Ala8 and Glu9 . This cleavage event inactivates GLP‐1, and generates a species that acts as an antagonist at the GLP‐1R .…”

“…In addition, GLP‐1 is subject to rapid renal clearance, due to its lower molecular weight (e.g., <25 kDa) and hydrophilic nature, which makes it subject to clearance by glomerular filtration . Because of these factors, the circulation time of native GLP‐1 is short, which limits its clinical application as a treatment for T2DM . In comparison, a natural GLP‐1 mimetic peptide exendin‐4 has been isolated and marketed as a treatment for T2DM.…”