Design and Development of a New Glucagon-Like Peptide-1 Receptor Agonist to Obtain High Oral Bioavailability

Purpose: Semaglutide is the only oral GLP-1 RA in the market, but oral bioavailability is generally limited in range of 0.4-1%. In this study, a new GLP-1RA named SHR-2042 was developed to gain higher oral bioavailability than semaglutide.

Method: Self-association of SHR-2042, semaglutide and liraglutide were assessed using SEC-MALS. The intestinal perfusion test in SD rats was used to select permeation enhancers (PEs) including SNAC, C10 and LCC. ITC, CD and DLS were used to explore the interaction between SHR-2042 and SNAC. Gastric administrated test in SD rats was used to screen SHR-2042 granules with different SHR-2042/SNAC ratios. The oral bioavailability of SHR-2042 was studied in rats and monkeys.

Result: The designed GLP-1RA, SHR-2042, gives a better solubility and lipophilicity than semaglutide. While it forms a similar oligomer with that of semaglutide. During the selection of PEs, SNAC shows better exposure than the other competing PEs including C10 and LCC. SHR-2042 and SNAC bind quickly and exhibit hydrophobic interaction. SNAC could promote monomerization of SHR-2042 and form micelles to trap the monomerized SHR-2042. The oral bioavailability of SHR-2042 paired with SNAC is 0.041% (1:0, w/w), 0.083% (1:10, w/w), 0.32% (1:30, w/w) and 2.83% (1:60, w/w) in rats. And the oral bioavailability of SHR-2042 matched with SNAC is 3.39% (1:30, w/w) in monkeys, which is over 10 times higher than that of semaglutide.

Conclusion: We believe that the design and development of oral SHR-2042 will provide a new way to design more and more GLP-1RAs with high oral bioavailability in the future.

GLP-1RA; Monkeys; Oligomer; Oral bioavailability; Rats.