Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia

Abstract

Achondroplasia is caused by gain-of-function mutations in FGFR3 gene and leads to short-limb dwarfism. A stabilized analogue of C-type natriuretic peptide (CNP) is known to elongate bone by interacting with FGFR3 signals and thus is a promising drug candidate. However, it needs daily administration by percutaneous injection. FGFR inhibitor compounds are other drug candidates for achondroplasia because they directly fix the mutant protein malfunction. Although FGFR inhibitors elongate the bone of model mice, their adverse effects are not well studied. In this study, we found that a new FGFR inhibitor, ASP5878, which was originally developed as an anti-cancer drug, elongated the bone of achondroplasia model male mice at the dose of 300 μg/kg, which confers an AUC of 275 ng·h/ml in juvenile mice. Although ASP5878 was less effective in bone elongation than a CNP analogue, it is advantageous in that ASP5878 can be administered orally. The AUC at which minimal adverse effects were observed (very slight atrophy of the corneal epithelium) was 459 ng·h/ml in juvenile rats. The positive discrepancy between AUCs that brought efficacy and minimal adverse effect suggests the applicability of ASP5878 to achondroplasia in the clinical setting. We also analyzed effects of ASP5878 in a patient-specific induced pluripotent stem cell (iPSC) model for achondroplasia and found the effects on patient chondrocyte equivalents. Nevertheless, cautious consideration is needed when referring to safety data obtained from its application to adult patients with cancer in clinical tests.

New developments in the biology of fibroblast growth factors

“…A relatively large number of additional small-molecule FGFR inhibitors have been developed and are being evaluated for genetic and physiological diseases and cancer (Al-Obaidy & Cheng, 2021;Chioni & Grose, 2021;Weaver & Bossaer, 2021). For example, in preclinical models, ASP5878 and Infigratinib (BGJ398) show efficacy in a mouse model for Achondroplasia, which is caused by activating mutations in FGFR3 (Komla-Ebri et al, 2016;Ornitz & Legeai-Mallet, 2017;Ozaki et al, 2020). However, in a mouse model of pulmonary fibrosis, Infigratinib reduced fibrosis, but also inhibited epithelial homeostasis and repair, leading to increased mortality (Morizumi et al, 2020), demonstrating the need for more selective FGFR inhibitors or cell-type-specific targeting.…”

Long-term oral meclozine administration improves survival rate and spinal canal stenosis during postnatal growth in a mouse model of achondroplasia in both sexes

“…ASP5878, an orally administered pan-specific FGFR inhibitor originally developed as an anticancer drug, 38 enhances bone growth in Fgfr3 ach mice. 39 Further research with ASP5878 is needed before it can be applied in clinical settings. In contrast, meclozine has been used in children for anti-motion sickness for more than 50 yr. 40 There were no reports of severe adverse events after repeated doses of meclozine (25 mg/d) for 3 mo in patients with developmental dyslexia aged 9–14 yr. 41 In our previous pharmacokinetic analyses, 16 the peak drug concentration (C max ) and area under the concentration-time curve of 2 mg/kg meclozine in mice were lower than those obtained with 25 mg/kg/d in adult humans, 42 which is the dose used for the treatment of motion sickness.…”

Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review

“…The inhibitor effect was analyzed and determined to be less effective for targeting bone elongation than the CNP analog. However, attention was drawn to the possibility of oral ASP5878 administration, which may reduce the stress and inconvenience associated with multiple subcutaneous injections of the CNP analog in pediatric patients suffering from achondroplasia [ 86 ].…”

“…The use of ASP5878 increased the thickness of the growth plate. Moreover, when examining iPSC cells, an effect on chondrocyte equivalents was found [ 86 ].…”

“…The authors of the publication recommend caution due to the emerging atrophy of the corneal epithelium in mice and the increased frequency of quite numerous side effects during the use of the drug in adult cancer patients [ 86 ].…”