OR21-05 Low-dose Infigratinib, An Oral Selective Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor, Demonstrates Activity In Murine Models Of Achondroplasia And Hypochondroplasia

Disclosure: E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. B. Demuynck: None. L. Loisay: None. M. Paull: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. L. Legeai-Mallet: None. Background: FGFR3 is a negative regulator of bone growth and gain-of-function mutations in the FGFR3 gene result in different skeletal osteochondrodysplasias, including achondroplasia (ACH) and hypochondroplasia (HCH). ACH is the most common form of rhizomelic short stature, affecting between 1 in 15,000 and 1 in 30,000 live births worldwide. The incidence of HCH is thought to be approximately the same as ACH. Currently, there is only one approved therapy for ACH and no approved therapies for HCH. Previously we demonstrated that the oral, selective FGFR 1-3 tyrosine kinase inhibitor (TKI) infigratinib has preclinical activity in a mouse model mimicking ACH (Fgfr3(Y367C/+)). We hypothesized that infigratinib could improve defective endochondral ossification and ameliorate the phenotype in a mouse model of HCH (Fgfr3(N534K/+)), which is the first and only HCH mouse model that expresses the most frequent human heterozygous mutation p.Asn540Lys.Methods:Fgfr3(N534K/+) mice were given subcutaneous injections of infigratinib or vehicle control every 3 days (1 mg/kg) or daily (1 mg/kg) for 15 days (post-natal day [PND] 4-19) or 21 days (PND 3-24), respectively. Results:Fgfr3(N534K/+) mice treated with 1 mg/kg infigratinib daily for a total of 21 days showed a statistically significant increase in appendicular and axial skeleton (tibia +3.18%, femur +3.16%, humerus +3.04%, ulna +2.94%, radius +3.01%). Treatment with infigratinib modified skull shape, length of the mandible, and foramen magnum length (+3.72%). Cartilage growth plate organization, in particular the hypertrophic chondrocyte area, was modified, indicating that chondrocyte differentiation is improved. These results, although of a lower magnitude, are in line with those previously reported from the Fgfr3(Y367C/+) mouse model of ACH, which showed a statistically significant improvement in upper limbs (humerus +7.3%, ulna +11.1%, radius +14.2 %), lower limbs (femur +10.4%, tibia +16.8%), and foramen magnum length (+3.76%), when infigratinib was administered at a dose of 0.5 mg/kg. Conclusions: Low-dose treatment with infigratinib in the Fgfr3(N534K/+) HCH mouse model ameliorated the clinical hallmarks of human pathology and significantly lengthened the axial skeleton, the appendicular skeleton and improved foramen magnum length. Development of infigratinib in ACH is currently ongoing. These latest findings with infigratinib in this mouse model of HCH support the rationale for targeting FGFR3 with a specific TKI such as infigratinib for the treatment of children with HCH. Presentation: Saturday, June 17, 2023