SUN-098 Low-Dose Infigratinib Treatment Does Not Lead to Changes in Phosphorous Preclinically in Mice

BACKGROUND: Infigratinib (BGJ398) is a potent and selective FGFR1-3 inhibitor under evaluation for the treatment of achondroplasia, the most common form of disproportionate short stature. Low doses of infigratinib were shown to be effective in improving skeletal abnormalities in a mouse model of achondroplasia [Demuynck et al. 2019; Komla-Ebri et al. 2016]. At higher doses in adult patients (e.g. 10-100-fold the dose shown to have efficacy in preclinical models of achondroplasia) infigratinib appears to be associated with elevation in phosphorus, an effect known to be associated with FGFR1 inhibition. Specifically, FGFR1 inhibition leads to decreases in FGF23, which, in turn, leads to decreased excretion of phosphate by the kidneys. We sought to understand the relationship between lower doses of infigratinib and changes in phosphorus in preclinical animal models. Methods: Changes in phosphorus were tested at multiple doses in three different species - mouse, rat, and dog - across five different studies. Infigratinib was given orally at doses ranging from 0.03 mg/kg to 30 mg/kg. Both PK and PD (i.e., phosphorus) data was available in all species. Measurement days ranged from day 10 to week 12, although PK/PD measurements occurred within 1 day of each other. All animals were treated in accordance with AVMA guidelines. Results: No significant dose-phosphorus relationship was observed in rats and mice treated with doses of infigratinib ranging from 0.03 mg/kg to 5 mg/kg. A dose-phosphorus and exposure (AUC(0-24))-phosphorus relationship was observed at doses of infigratinib ≥10 mg/kg across transgenic mouse, rat, and dog studies. At low doses, the exposure (AUC(0-24))-phosphorus relationship showed a shallow slope with linear regression analysis in rats and mice. Conclusions: These findings from five studies in three different species indicate that the exposure-phosphorus relationship is consistent. Importantly, no relationship was observed between dose and phosphorus levels in rats and mice treated with infigratinib at or below 5 mg/kg. Despite the fact that infigratinib is a FGFR1, 2 and 3 inhibitor, low doses of infigratinib shown previously to exert a significant effect in improving skeletal abnormalities in an achondroplasia mouse model, do not seem to result in meaningful changes in phosphorus. These experiments demonstrate that at doses of infigratinib much lower than used in oncology - like those being considered for use in clinical studies of achondroplasia - infigratinib is less likely to cause hyperphosphatemia. Infigratinib will be evaluated in global clinical studies in children with achondroplasia in 2020.