ESPEYB25 5. Bone, Growth Plate and Mineral Metabolism Novel Treatments (6 abstracts)
5.11. Oral infigratinib therapy in children with achondroplasia
Savarirayan R , De Bergua JM , Arundel P , Salles JP , Saraff V , Delgado B , Leiva-Gea A , McDevitt H , Nicolino M , Rossi M , Salcedo M , Cormier-Daire V , Skae M , Kannu P , Phillips J , Saal H , Harmatz P , Candler T , Hill D & Rogoff D
The New England Journal of Medicine. 2025.392(9):865-874. PMID: 39555818 https://doi.org/10.1056/NEJMoa2411790
Brief Summary: This Phase 2 dose-finding study evaluated the safety and efficacy of oral infigratinib in children aged 3 to 11 with achondroplasia. Infigratinib was generally well tolerated and that, at the highest dose, it increased annualised height velocity and improved body proportions over 18 months.
Commentary: Achondroplasia, the most common form of disproportionate short stature, is caused by gain-of-function pathogenic variants in the FGFR3 gene. This leads to impaired endochondral ossification and various medical complications. Infigratinib is an orally bioavailable, selective tyrosine kinase inhibitor of FGFR1-3 that directly targets the underlying pathophysiological mechanism by inhibiting FGFR phosphorylation and attenuating downstream signalling pathways.
This study shows that infigratinib is well tolerated orally, with mostly mild or moderate adverse events that did not lead to treatment discontinuation, and that it effectively promotes linear growth. Specifically, the highest dose (0.25 mg per kilogram) led to a sustained increase in annualised height velocity (mean change from baseline at 18 months: 2.5 cm per year) and a decrease in the upper-to-lower body segment ratio, thereby addressing the characteristic disproportion in achondroplasia. This is particularly noteworthy given that previous oncology studies used much higher doses; this study confirms the efficacy of significantly lower, safer levels for children. The positive results of this phase 2 study, particularly with regard to efficacy and the safety profile, must be confirmed in a phase 3 trial in order to evaluate infigratinib further in a larger cohort of children.
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.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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