Infigratinib shows promising efficacy and tolerability in pediatric achondroplasia

1. In this phase two dose-finding study in children with achondroplasia, daily oral Infigratinib did not lead to any grade 4 or 5 adverse events.

2. Infigratinib treatment led to a sustained increase in annualized height velocity and a reduction in upper-to-lower body segment ratios.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Achondroplasia is caused by an inherited gain-of-function pathogenic variant in FGFR3, the gene encoding fibroblast growth factor receptor 3, which leads to impaired endochondral ossification. Currently, the only approved therapy is vosoritide, administered as a daily subcutaneous injection, and no established oral treatment exists. Infigratinib is an FGFR1-3 selective tyrosine kinase inhibitor that remains bioavailable when taken orally. By inhibiting FGFR phosphorylation, it downregulates downstream signaling pathways such as the STAT1 and MAPK pathways. Previously, Infigratinib has been assessed in FGFR-associated cancers and animal models, demonstrating promising results. This study aimed to determine an appropriate dose of Infigratinib for future research and to evaluate its safety and efficacy in children aged 3 to 11 years with achondroplasia. All enrolled patients experienced at least one adverse event; however, no grade 4 or 5 adverse events were reported. Notably, the frequency and severity of adverse events remained relatively consistent across all Infigratinib doses. A dose-dependent relationship was established between Infigratinib dosage and height growth rate. Although this study was limited by its small sample size, it demonstrates that Infigratinib has a mild side-effect profile and may provide sustained height growth velocity in children with achondroplasia.

Click here to read the study in NEJM

Relevant Reading: Oral Infigratinib in Children with Achondroplasia — Targeted Treatment

In-Depth [dose-finding study]: This phase two dose-finding study aimed to establish an appropriate Infigratinib dosage for future research in pediatric achondroplasia by conducting preliminary safety and efficacy assessments. Eligibility criteria included children aged 3 to 11 years with a genetically confirmed diagnosis of achondroplasia. Exclusion criteria included a height more than ±2 SD from the mean on achondroplasia growth charts, an annualized height velocity of 1.5 cm per year or less, prior treatment with another investigational achondroplasia therapy, or a history of limb-lengthening surgery. A total of 72 patients were enrolled and assigned to five cohorts, each receiving a different Infigratinib dose: Cohort 1 received 0.016 mg/kg, Cohort 2 received 0.032 mg/kg, Cohort 3 received 0.064 mg/kg, Cohort 4 received 0.128 mg/kg, and Cohort 5 received 0.25 mg/kg. All patients experienced at least one adverse event; however, in 54% of cases, the worst adverse event was mild. The most common side effect was nasopharyngitis, occurring in 40% of participants. A dose-dependent increase in annualized height velocity was observed. After six months, patients in Cohort 1 experienced a -1.82 cm per year change in height velocity (95% confidence interval [CI], -4.96 to 1.32), while those in Cohort 5 had a 3.38 cm per year change (95% CI, 1.67 to 5.10). This increase in height velocity in Cohort 5 was sustained through 18 months, with an average change from baseline of 2.50 cm per year at this time (95% CI, 1.22 to 3.79; p=0.001). This correlated with a z-score increase of 0.54 (95% CI, 0.35 to 0.72) on achondroplasia-specific growth charts. Additionally, the upper-to-lower body segment ratio decreased by 0.12 (95% CI, -0.18 to -0.06) at 18 months, suggesting proportional growth improvements. These findings highlight Infigratinib’s mild safety profile and potential efficacy as an oral treatment for pediatric achondroplasia.

Image: PD

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