SUN-087 FGFR-Selective Tyrosine Kinase Inhibitors Such as Infigratinib Show Potency and Selectivity for FGFR3 at Pharmacologically Relevant Doses for the Potential Treatment of Achondroplasia

摘要

BACKGROUND: Germline mutations in fibroblast growth factor receptor (FGFR) genes 1-3 can cause skeletal dysplasias and craniosynostoses. Achondroplasia (ACH), the most common form of disproportionate short stature, is caused primarily by an autosomal dominant G380R substitution in FGFR3 [Horton WA et al. Lancet 2007]. Infigratinib (BGJ398), a potent and selective FGFR1-3 tyrosine kinase inhibitor (TKI), demonstrated preclinical efficacy at low doses in an ACH mouse model [Demuynck et al. 2019; Komla-Ebri et al. 2016]. The objective of this analysis is to evaluate the dose dependency and toxicity profiles of FGFR-selective TKIs like infigratinib in preclinical skeletal dysplasia models. Methods: A review of the literature was performed to investigate non-clinical data from studies of infigratinib and other FGFR-selective TKIs relevant to FGFR-driven skeletal dysplasias. Major databases (e.g., PubMed, Medline [NLM Catalog]) were searched for relevant articles from the past 10 years and conference archives (e.g., ENDO, ESPE, ISDS, ASHG, ASBMR) for relevant abstracts from the past 5 years. Full text was included where possible. Key words included in the searches were based on the following: achondroplasia, FGFR inhibition, infigratinib, BGJ398, tyrosine kinase inhibitor. Results: Of the 683 publications identified, 10 relevant articles and 2 abstracts were selected for review. Due to direct relevance, 2 additional articles were included, bringing the total to 14 publications. Key results from studies of infigratinib, the most commonly identified TKI, included: FGFR3 IC50 1.0 nM, FGFR3-K650E IC50 4.9 nM. In vitro data showed inhibition of FGFR1-3 activity at concentrations of 5 to 100 nM, including reversal of established growth arrest in chondrocytes at 7 nM. In vivo studies revealed dose-dependent improvements in foramen magnum and long bone length in Fgfr3Y367C/+ mice at doses of 0.2-2 mg/kg/day. No studies reported a survival disadvantage and one showed a significant survival advantage for infigratinib-treated ACH mice. In relation to other FGFR TKIs, one study showed that AZD4547 decreased survival in mice treated at doses of 1x106 to 2x106 nM, and another showed limb malformation in chicken embryos treated with PD173074 at doses of 1x106 to 50x106 nM. While one study suggested toxicity with infigratinib and other FGFR-selective TKIs, the results were not produced at pharmacologically relevant doses for ACH nor were they replicated in the literature. Furthermore, in vivo studies reporting treatment in mice with low doses of infigratinib did not result in any of the abnormal findings observed in this study. Conclusions: Recent studies indicate preclinical efficacy of infigratinib, including a survival advantage in Fgfr3Y367C/+ mice. Given the totality of evidence, low-dose infigratinib appears to be a potentially safe option for further development in children with ACH.