Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes

Abstract

Background Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP-1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials. Methods In a single-dose, first-inhuman trial, 135 healthy males received oral semaglutide (2-20 mg semaglutide coformulated with 150-600 mg SNAC) or placebo with SNAC. In a 10-week, once-daily, multiple-dose trial, 84 healthy males received 20 or 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC, and 23 males with type 2 diabetes (T2D) received 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC. Results Oral semaglutide was safe and well-tolerated in both trials. The majority of adverse events (AEs) were mild, with the most common AEs being gastrointestinal disorders. In the single-dose trial, semaglutide exposure was highest when coformulated with 300 mg SNAC. In the multiple-dose trial, semaglutide exposure was approximately twofold higher with 40 versus 20 mg oral semaglutide in healthy males, in accordance with dose proportionality, and was similar between healthy males and males with T2D. The half-life of semaglutide was approximately 1 week in all groups. Conclusion The safety profile of oral semaglutide was as expected for the GLP-1 receptor agonist drug class. Oral semaglutide co-formulated with 300 mg SNAC was chosen for further clinical development. The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing. ClinicalTrials.gov identifiers NCT01037582, NCT01686945.

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

“…Once absorbed, s.c. and oral semaglutide share similar pharmacokinetic profiles and effects . It has been shown that median exposure of s.c. semaglutide 1.0 mg is higher than oral semaglutide 14 mg.…”

Incretins in obesity and diabetes

“…The size of the compound, at 59.7 kDa, reduces its renal clearance. 206 Similar to injectable semaglutide, oral semaglutide has a half-life of about 7 days, and an FDA New Drug Application was submitted in March 2019. 202 Similar to albiglutide, these modifications extended the half-life of dulaglutide to about 5 days allowing for once weekly administration.…”

“…Furthermore, the amino acid sequence of the GLP-1 analog has been modified at three positions-substitution of Ala 8 with Gly 8 , Gly 22 to Glu 22 , and Arg 36 to Gly 36to prevent DPP-4 hydrolysis. 206,207 The fifth long-acting GLP-1R agonist is a sustained-release formulation of exenatide consisting of injectable microspheres of exenatide and poly (d,l lactic-co-glycolic acid), a common biodegradable medical polymer with established use in absorbable sutures and extended release pharmaceuticals, that allows gradual drug delivery at a controlled rate. 203 The synthesis of semaglutide was based on liraglutide.…”

“…An oral form of semaglutide is under development, where semaglutide is coformulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) to facilitate its absorption across the gastric epithelium. 206 Similar to injectable semaglutide, oral semaglutide has a half-life of about 7 days, and an FDA New Drug Application was submitted in March 2019. 206,207 The fifth long-acting GLP-1R agonist is a sustained-release formulation of exenatide consisting of injectable microspheres of exenatide and poly (d,l lactic-co-glycolic acid), a common biodegradable medical polymer with established use in absorbable sutures and extended release pharmaceuticals, that allows gradual drug delivery at a controlled rate.…”

“…206 Similar to injectable semaglutide, oral semaglutide has a half-life of about 7 days, and an FDA New Drug Application was submitted in March 2019. 206,207 The fifth long-acting GLP-1R agonist is a sustained-release formulation of exenatide consisting of injectable microspheres of exenatide and poly (d,l lactic-co-glycolic acid), a common biodegradable medical polymer with established use in absorbable sutures and extended release pharmaceuticals, that allows gradual drug delivery at a controlled rate. 208,209 GLP-1R agonist via infusion pump.…”