IMPE Abstracts

Background: FGFR3 is a negative regulator of bone growth. 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 none for HCH. Previously we demonstrated that infigratinib showed preclinical efficacy in a mouse model mimicking ACH (Fgfr3^Y367C/+). In this preclinical study, we hypothesized that the oral, selective FGFR 1–3 tyrosine kinase inhibitor (TKI) 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 received 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 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 a mouse model of ACH (Fgfr3^Y367C/+), 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 this 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 an Fgfr3^N534K/+mouse model of HCH support the rationale for targeting FGFR3 with a specific TKI such as infigratinib for the treatment of children with HCH.