Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease

Abstract

Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is challenged by gastrointestinal instability and ineffective uptake into the circulation. Here, we have used glucagon-like peptide-1 (GLP-1) as a model peptide therapeutic for treating obesity-linked type 2 diabetes, a common chronic disease. We describe a comprehensive multidisciplinary approach leading to the development of MEDI7219, a GLP-1 receptor agonist (GLP-1RA) specifically engineered for oral delivery. Sites of protease/peptidase vulnerabilities in GLP-1 were removed by amino acid substitution and the peptide backbone was bis-lipidated to promote MEDI7219 reversible plasma protein binding without affecting potency. A combination of sodium chenodeoxycholate and propyl gallate was used to enhance bioavailability of MEDI7219 at the site of maximal gastrointestinal absorption, targeted by enteric-coated tablets. This synergistic approach resulted in MEDI7219 bioavailability of ~ 6% in dogs receiving oral tablets. In a dog model of obesity and insulin resistance, MEDI7219 oral tablets significantly decreased food intake, body weight and glucose excursions, validating the approach. This novel approach to the development of MEDI7219 provides a template for the development of other oral peptide therapeutics.

Intestinal Absorption of FITC-Dextrans and Macromolecular Model Drugs in the Rat Intestinal Instillation Model

“…The stability of MEDI7219 in simulated intestinal fluid containing pancreatin was inferred from the published literature, showing that 90% of the peptide remained intact over a 60 min period. 10 In a study by Mehvar and Shepard, FITC-dextrans were administered orally to rats and the excreted FITC-dextrans were analyzed from urine. 22 The molecular weights of the excreted FITC-dextran 4000 and FITC-dextran 20 000 were similar to that of the administered dextrans, indicating that these FITC-dextrans are not degraded to any significant extent in the gastrointestinal tract.…”

“…MEDI7219 is a glucagon-like peptide 1 (GLP-1) receptor agonist drug candidate developed by AstraZeneca. 10 The peptide was designed for oral delivery and has natural amino acid and α-methyl amino acid substitutions to protect against peptidasesin the gastrointestinal tract. The peptide backbone has two lipid side chains that can bind to plasma proteins, thereby prolonging the circulation half-life of the peptide.…”

“…MEDI7219 is a glucagon-like peptide 1 (GLP-1) receptor agonist drug candidate developed by AstraZeneca . The peptide was designed for oral delivery and has natural amino acid and α-methyl amino acid substitutions to protect against peptidasesin the gastrointestinal tract.…”

Bioanalytical Methods and Strategic Perspectives Addressing the Rising Complexity of Novel Bioconjugates and Delivery Routes for Biotherapeutics

“…Some examples include cyclization of peptides to increase stability and the introduction of unnatural amino acids such as α,α-disubstituted amino acids to protect vulnerable proteolytic sites [120,121]. Lipidation or use of nonproteinogenic amino acid may also contribute to the stability of the molecule [122,123]. While increasing the stability of the compound, these modifications may affect the physicochemical properties of the compound and thus require novel bioanalytical approaches.…”

Design of Potent and Proteolytically Stable Biaryl-Stapled GLP-1R/GIPR Peptide Dual Agonists

“…In addition, it must be taken on an empty stomach, and for 30 min after taking oral semaglutide, no other food, drink, or medication can be taken to permit undisturbed absorption. To get around this complex dosing scheme, a multifaceted approach combining amino acid backbone α-methylation and 25 suggesting chemical modifications may be needed for more conventional oral administration of peptide drugs. Since GLP-1 and GIP bind to their cognate receptors in an α-helical conformation, 26,27 modifications that stabilize peptide α-helix should increase their binding affinity and improve their proteolytic stability.…”