2FA-Platform Generates Dual Fatty Acid-Conjugated GLP‑1 Receptor Agonist TE-8105 with Enhanced Diabetes, Obesity, and NASH Efficacy Compared to Semaglutide

Conjugating two fatty acids (2FAs) to peptide drugs can
improve
pharmacokinetics and therapeutic effects. However, optimizing FA spacing,
chain combination, and attachment site to simultaneously enhance albumin
binding and drug efficacy remains challenging. We introduce a multiarm
linker technology enabling precise control of 2FA spacing, composition,
and attachment. By applying this technology to a modified glucagon-like
peptide-1 (GLP-1) and screening various 2FA-GLP-1 conjugates differing
in linkage, linker, and FA properties for improved albumin affinity,
pharmacokinetics, and pharmacodynamics, TE-8105 emerged as a promising
candidate. TE-8105 outperformed semaglutide, showing improved long-term
glycemic control, weight loss, and liver health in diabetic mice,
and dose-dependent weight loss and favorable body composition changes
in obese mice. A distinct advantage of TE-8105 over semaglutide is
its low-dose reduction of liver steatosis and improvement of liver
health in nonalcoholic steatohepatitis mice. The multiarm linker technology
provides a versatile platform for developing improved 2FA-peptide
therapeutics.