ESPE Abstracts

Achondroplasia (ACH) is the most common human skeletal dysplasia caused by gain -of-function mutation in the fibroblast growth factor receptor gene (FGFR) 3-encoding protein. Vosoritide, an analog of C-type natriuretic peptide (CNP), is currently the sole medication approved for ACH treatment. Vosoritide can only be administered by daily injection, leaving room for improvement. Infigratinib, a pan-FGFR1/2/3 inhibitor, offers a potential oral treatment alternative and is currently undergoing clinical trials for ACH. Here, we reported the identification and pharmacological characterization of a pre-clinical candidate compound GSC000829, exhibiting a strong inhibition towards FGFR3 and a significantly improved selectivity over FGFR1 and FGFR4. The improvement in selectivity translated into a much better safety window in toxicology studies as compared to other pan-FGFR inhibitors. GSC000829 effectively reversed ex vivo FGF-induced femur growth arrest and promoted chondrocytes development. Significant elongation in overall body length as well as improvement of growth plate architecture were observed in FGFR3-mutated achondroplasia mice model following a 14-day treatment regimen with oral dosage of GSC000829. GSC000829 exhibits favorable physicochemical and pharmacokinetic properties along with an excellent preclinical toxicity profile. GSC000829 is under IND-enabling studies and scheduled to enter clinical development in early 2025.