ESPE Yearbook of Paediatric Endocrinology

In brief: This study investigated the effect of infigratinib, a selective and orally bioavailable FGFR1-3 inhibitor, administered at different doses or according to different dosing regimens, on bone growth in a mouse model mimicking achondroplasia (Fgfr3^Y367C/+). This study was partially sponsored by a grant from BridgeBio/QED Therapeutics.

Commentary: Achondroplasia is one of the most common constitutional bone diseases (> 300,000 affected individuals worldwide). It is associated with skeletal defects (disproportionate short stature, abnormal curvature of the spine, genu varum) but also with extra-skeletal manifestations (reduction of the upper airway with otitis and apnoea, stenosis of the foramen magnum and lumbar canal with spinal cord compression, hypotonia and muscle weakness) with the potential for functional limitations and psychosocial challenges. Achondroplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, resulting in impaired endochondral ossification.

Infigratinib is an orally bioavailable, selective FGFR tyrosine kinase inhibitor being developed for the treatment of FGFR-driven cancers such as cholangiocarcinoma and urothelial carcinoma. Using a mouse model mimicking achondroplasia, it was previously reported that daily treatment with infigratinib at a dose of 2 mg/kg significantly increased bone growth. In the present study, lower doses (0.2 and 0.5 mg/kg, given once daily) were sufficient to observe significant improvements in axial and appendicular skeletal growth and skull development. In addition, analyses showed an increase in the area of the foramen magnum at the base of the skull, improving foramen magnum stenosis, a well-recognised complication of achondroplasia. This proof-of-concept study shows that low-dose infigratinib has the potential to be a safe and effective treatment option for children with achondroplasia.

Phase 2 and 3 clinical trials are currently underway to test the efficacy of infigratinib in children with acondroplasia. Recently announced results of a Phase 2 study of infigratinib in children with achondroplasia demonstrated a significant and robust increase in annualized height velocity, with a mean change of 3.38 cm/year from baseline, and no treatment–related adverse effects ¹.

Various therapeutic trials are currently being evaluated in achondroplasia (vosoritide, TransCon CNP, infigratinib). It will be important to determine the relative efficacy of these different treatments in the future, and also to evaluate therapies combining these compounds.

Reference: 1. Savarirayan R, De Bergua JM, Arundel P, et al. OR27-03 oral Infigratinib treatment is well tolerated and significantly increases height velocity in children with achondroplasia: month 6 results from the PROPEL 2 dose finding study. J Endocr Soc. 2023;7(Supplement_1):A814. doi: https://doi.org/10.1210/jendso/bvad114.1525