ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 5.2 | DOI: 10.1530/ey.18.5.2

Cell Induction and Regulation Field, Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Japan.

Sci Rep. 2020 Dec 1;10(1):20915 Abstract:

In brief: Inhibition of excessive FGFR3 signalling constitutes the key mechanism of pharmacological treatments in achondroplasia. In this pharmacokinetic and pharmacodynamic animal study, the FGFR inhibitor ASP5878 with potential oral application mode revealed beneficial effects on skeletal growth in achondroplasia mice.

Comment: Multiple strategies for treatment of achondroplasia by inhibition of excessive FGFR3 signalling are subject to clinical and basic research. So far, CNP analogues acting at the MAPK level downstream of FGFR3 have been shown the most promising results with positive phase II & III trial results and likely imminent approval of Vosoritide and on-going Phase II trials of TransCon-CNP as the most promising agents.

Pan-FGFR blockers were originally developed as oncological treatments of FGF receptor expressing tumours. Here, Ozaki et al. investigated the effects of the novel FGFR-blocker ASP5878 for pharmacodynamic studies in an achondroplasia model system. Comparative analysis with a vosoritide-like peptide treatment as “gold-standard” of FGFR3 inhibition has been performed. The study showed amelioration of bone length and growth plate thickness in male mice, although CNP analogues revealed superior results. Interestingly, the effect was weaker in female mice.

Several FGFR-inhibiting molecules with potential to effectively inhibit the overactive FGFR3 receptor in achondroplasia have been investigated in achondroplasia animal models (reviewed in 1). However, pan-FGFR inhibition commonly has adverse effects on other organ systems. The authors have therefore given special emphasis on off-target effects. Despite of a quite favourable risk profile in this animal study, adverse effects in ASP5878-treated adult carcinoma patients including hyperphosphatemia and retinal detachment raise concerns for potential safety issues in the use of ASP5878 in paediatric patients.

Other potential treatments with oral administration include the antihistamine meclizine as well as the tyrosine kinase inhibitor infigratinib. Infigratinib is currently under investigation in phase II studies, whereas meclizine has completed phase I study showing promising safety data (2).

In conclusion, this study extends the spectrum of promising pharmacological candidates for medical treatment to improve skeletal growth in achondroplasia. The potential of oral administration is very attractive. However, concerns of limited efficacy and adverse effects may limit its prospects for future development to a safe and efficacious medicine that can be used to augment growth in children with FGFR3-related skeletal dysplasias.

Reference: 1. Wrobel, W., E. Pach, and I. Ben-Skowronek, Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review. Int J Mol Sci, 2021. 22(11).2. Kitoh, H., et al., Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia. PLoS One, 2020. 15(4): p. e0229639.

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