ESPE Abstracts

Background: Germline mutations in fibroblast growth factor receptor (FGFR) genes 1–3 can cause skeletal dysplasias such as achondroplasia (ACH), which is caused primarily by a G380R substitution in FGFR3. Infigratinib (BGJ398), a potent and selective FGFR1–3 tyrosine kinase inhibitor (TKI), demonstrated preclinical efficacy at low doses in an ACH mouse model. The objective of this analysis is to evaluate 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 FGFR-selective TKIs relevant to FGFR-driven skeletal dysplasias. Major databases (e.g., PubMed, Medline) were searched for relevant articles from the past decade 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 search terms were: achondroplasia, FGFR inhibition, infigratinib, tyrosine kinase inhibitor.

Results: Of 683 publications identified, 10 relevant articles and 2 abstracts were selected for review. Due to direct relevance, 5 additional publications were included (total 17 included). 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 5–100 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 Fgfr3^Y367C/+ mice at 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 these studies suggested toxicity with FGFR-selective TKIs, the studies were not conducted with pharmacologically relevant doses for ACH, nor were they replicated in the literature. In vivo studies reporting treatment in mouse models of ACH with low doses of infigratinib or ASP5878 did not result in any of these abnormal findings.

Conclusions: Recent studies indicate preclinical efficacy of infigratinib, including a survival advantage in Fgfr3^Y367C/+ mice. Given the totality of evidence, low-dose infigratinib appears to be a potentially safe option for further development in children with ACH.