EXT418

EXT418 is a novel long-acting, constitutively active ghrelin analog designed to overcome the short half-life of native ghrelin by covalent conjugation to a vitamin D derivative via a proprietary D-VITylation™ technology. This modification extends the circulating half-life by leveraging vitamin D binding protein (VDBP) association and prevents rapid renal clearance. EXT418 retains ghrelin’s orexigenic and anabolic properties but exhibits improved pharmacokinetics. In preclinical models, it has shown efficacy in mitigating cancer cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, and by partially preserving body weight, fat mass, lean mass, grip strength, and muscle fiber cross-sectional area, with some effects independent of food intake. The drug does not affect tumor mass. EXT418 is also being explored for diabetes-induced peripheral neuropathy due to ghrelin’s anti-inflammatory and neuroprotective effects. The molecular structure is hGhrelin(1–28)–(DAP-Oct)^3^–Cys^29^–PEG~36~–VitD, with a key modification replacing serine-3 with n-octanoylated 2,3-diaminopropionic acid (DAP) to prevent enzymatic deacylation and maintain constitutive activity. Efficacy studies are completed for cachexia, and the compound is IND-ready[1][5].