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Background: Achondroplasia (ACH) is the most common non-lethal skeletal dysplasia. Fibroblast growth factor receptor 3 (FGFR3) plays a crucial role in bone elongation, demonstrated by FGFR3 gain-of-function mutations in individuals with ACH and hypochondroplasia. Multiple therapeutic strategies have been considered for ACH, the most advanced is to employ an analog of C-type Natriuretic Peptide (CNP), which antagonizes the MAP kinase (MAPK) pathway. Here, we evaluated a therapeutic strategy that targets all pathways downstream of FGFR3 (e.g., STAT1), not just MAPK. We hypothesized that a very low dose of the oral selective FGFR1-3 tyrosine kinase inhibitor (TKI) infigratinib (BGJ398) would be able to improve defective bone elongation. We also hypothesized that infigratinib would have greater potency at lower concentrations in an ACH cell line than a CNP analog (e.g., vosoritide) given its effects on multiple downstream pathways. Methods: A mouse model (Fgfr3Y367C/+) mimicking ACH was treated with subcutaneous injections of infigratinib daily (0.2 or 0.5 mg/kg/day) or intermittently (1 mg/kg, every 3 days) for a treatment duration of 15 days (PND1-15). In vivo results were compared with vehicle-treated mutant mice. TAN 4-18-chondrocytes, a human chondrocyte line expressing a heterozygous Y373C FGFR3 mutation, were treated with multiple concentrations of infigratinib and vosoritide and MAPK levels were measured. Results: We observed a significant improvement of the upper (humerus +7%, ulna +11%) and lower (femur +11%, tibia +16%) limbs at 0.5 mg/kg/day, and improvement in the foramen magnum. The effect of infigratinib on bone elongation was reduced with a lower dose (0.2 mg/kg), confirming a dose-response relationship. With intermittent injections of infigratinib (1 mg/kg, every 3 days), gain of growth was significant for all the long bones (+7%) and the size of the foramen magnum was increased. Modification of the growth plate structure, displaying better organization, was also seen. In cell line data, compared with FGF18-treated TAN 4-18-chondrocytes, concentrations of 10-6M to 10-10M infigratinib led to statistically significant (p&amp;lt;0.05) improvements. With vosoritide treatment, a concentration of 10-4M led to statistically significant improvements compared with FGF18-treated chondrocytes (p&amp;lt;0.05), although this was not seen at 10-5M. Conclusions: Preclinical ACH mouse model data indicate that low, as well as intermittent, doses of infigratinib promote growth and can improve the foramen magnum. No apparent toxicity of infigratinib was observed, suggesting that TKI therapy has the potential to be a valuable and relevant option for children with ACH. Furthermore, cell line data indicate that infigratinib showed superior potency over a CNP analog, suggesting that inhibition of multiple FGFR3-related pathways vs MAPK inhibition alone may lead to increased efficacy.

SUN-101 Support for a New Therapeutic Approach of Using a Low-Dose FGFR Tyrosine Kinase Inhibitor (Infigratinib) for Achondroplasia